Cancer Genetics Risk Assessment and Counseling (PDQ®)–Health Professional Version

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Introduction

[Note: Many of the medical and scientific terms used in this summary are found in the NCI Dictionary of Genetics Terms. When a linked term is clicked, the definition will appear in a separate window.]

[Note: A concerted effort is being made within the genetics community to shift terminology used to describe genetic variation. The shift is to use the term “variant” rather than the term “mutation” to describe a difference that exists between the person or group being studied and the reference sequence. Variants can then be further classified as benign (harmless), likely benign, of uncertain significance, likely pathogenic, or pathogenic (disease causing). Throughout this summary, we will use the term pathogenic variant to describe a disease-causing mutation. Refer to the Cancer Genetics Overview summary for more information about variant classification.]

This summary describes current approaches to assessing and counseling people about their chance of having an inherited susceptibility to cancer. Genetic counseling is defined by the National Society of Genetic Counselors as the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease. Several reviews present overviews of the cancer risk assessment, counseling, and genetic testing process.[1,2]

Individuals are considered to be candidates for cancer risk assessment if they have a personal and/or family history (maternal or paternal lineage) with features suggestive of hereditary cancer.[1] These features vary by type of cancer and specific hereditary syndrome. Criteria have been published to help identify individuals who may benefit from genetic counseling.[1,3] The PDQ cancer genetics information summaries on breast, ovarian, endometrial, colorectal, prostate, kidney, and skin cancers and endocrine and neuroendocrine neoplasias describe the clinical features of hereditary syndromes associated with these conditions.

The following are features that suggest hereditary cancer:

  • Unusually early age of cancer onset (e.g., premenopausal breast cancer).
  • Multiple primary cancers in a single individual (e.g., colorectal and endometrial cancer).
  • Bilateral cancer in paired organs or multifocal disease (e.g., bilateral breast cancer or multifocal renal cancer).
  • Clustering of the same type of cancer in close relatives (e.g., mother, daughter, and sisters with breast cancer).
  • Cancers occurring in multiple generations of a family (i.e., autosomal dominant inheritance).
  • Occurrence of rare tumors (e.g., retinoblastoma, adrenocortical carcinoma, granulosa cell tumor of the ovary, ocular melanoma, or duodenal cancer).
  • Unusual presentation of cancer (e.g., male breast cancer).
  • Uncommon tumor histology (e.g., medullary thyroid carcinoma).
  • Rare cancers associated with birth defects (e.g., Wilms tumor and genitourinary abnormalities).
  • Geographic or ethnic populations known to be at high risk of hereditary cancers. Genetic testing candidates may be identified based solely on ethnicity when a strong founder effect is present in a given population (e.g., Ashkenazi heritage and BRCA1/BRCA2 pathogenic variants).[4-6]

As part of the process of genetic education and counseling, genetic testing may be considered when the following factors are present:

  • An individual's personal history (including ethnicity) and/or family history are suspicious for a genetic predisposition to cancer.
  • The genetic test has sufficient sensitivity and specificity to be interpreted.
  • The test will impact the individual's diagnosis, cancer management or cancer risk management, and/or help clarify risk in family members.[7-9]

It is important that individuals who are candidates for genetic testing undergo genetic education and counseling before testing to facilitate informed decision making and adaptation to the risk or condition.[1] Genetic education and counseling allows individuals to consider the various medical uncertainties, diagnosis, or medical management based on varied test results, and the risks, benefits, and limitations of genetic testing.

References
  1. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
  2. Weitzel JN, Blazer KR, MacDonald DJ, et al.: Genetics, genomics, and cancer risk assessment: State of the Art and Future Directions in the Era of Personalized Medicine. CA Cancer J Clin 61 (5): 327-59, 2011 Sep-Oct. [PUBMED Abstract]
  3. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
  4. Tobias DH, Eng C, McCurdy LD, et al.: Founder BRCA 1 and 2 mutations among a consecutive series of Ashkenazi Jewish ovarian cancer patients. Gynecol Oncol 78 (2): 148-51, 2000. [PUBMED Abstract]
  5. Beller U, Halle D, Catane R, et al.: High frequency of BRCA1 and BRCA2 germline mutations in Ashkenazi Jewish ovarian cancer patients, regardless of family history. Gynecol Oncol 67 (2): 123-6, 1997. [PUBMED Abstract]
  6. Gabai-Kapara E, Lahad A, Kaufman B, et al.: Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A 111 (39): 14205-10, 2014. [PUBMED Abstract]
  7. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
  8. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
  9. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]

Cancer Risk Assessment and Counseling

Comprehensive cancer risk assessment is a consultative service that includes clinical assessment, genetic testing when appropriate, and risk management recommendations delivered in the context of one or more genetic counseling sessions. Pretest genetic counseling is an important part of the risk assessment process and helps patients understand their genetic testing options and potential outcomes. Posttest genetic counseling helps patients understand their test results, including the medical implications for themselves and their relatives.

Several professional organizations emphasize the importance of genetic counseling in the cancer risk assessment and genetic testing process. Examples of these organizations include the following:

  • American College of Medical Genetics and Genomics.[1]
  • American Society of Clinical Oncology.[2,3]
  • American Society of Human Genetics.[4,5]
  • International Society of Nurses in Genetics.[6,7]
  • National Society of Genetic Counselors.[8-10]
  • National Comprehensive Cancer Network.[11,12]
  • Oncology Nursing Society.[13]
  • Society of Gynecologic Oncologists.[14]

A list of organizations that have published clinical practices guidelines related to genetic counseling, risk assessment, genetic testing, and/or management for hereditary breast and ovarian cancers is available in the PDQ summary on Genetics of Breast and Gynecologic Cancers.

Genetic counseling informs the consultand about potential cancer risks and the benefits and limitations of genetic testing and offers an opportunity to consider the potential medical, psychological, familial, and social implications of genetic information.[8,15] Descriptions of genetic counseling and the specialized practice of cancer risk assessment counseling are detailed below.

Genetic Counseling

Genetic counseling has been defined by the American Society of Human Genetics as “a communication process that deals with the human problems associated with the occurrence, or risk of occurrence, of a genetic disorder in a family." The process involves an attempt by one or more appropriately trained persons to help the individual or family do the following:

  1. Comprehend the medical facts, including the diagnosis, probable course of the disorder, and the available management.
  2. Appreciate the way that heredity contributes to the disorder, and to the risk of recurrence (occurrence), in specific relatives.
  3. Understand the alternatives for dealing with the risk of recurrence (occurrence).
  4. Choose a course of action that seems to them appropriate in view of their risk, their family goals, and their ethical and religious standards and act in accordance with that decision.
  5. Make the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence (occurrence) of that disorder.[16]

In 2006, the National Society of Genetic Counselors further refined the definition of genetic counseling to include the process of helping people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, including integration of the following:

  • Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence.
  • Education about inheritance, testing, management, prevention, resources, and research.
  • Counseling to promote informed choices and adaptation to the risk or condition.[8]

Central to the philosophy and practice of genetic counseling are the principles of voluntary utilization of services, informed decision making, attention to psychosocial and affective dimensions of coping with genetic risk, and protection of patient confidentiality and privacy. This is facilitated through a combination of rapport building and information gathering; establishing or verifying diagnoses; risk assessment and calculation of quantitative occurrence/recurrence risks; education and informed consent processes; psychosocial assessment, support, and counseling appropriate to a family’s culture and ethnicity; and other relevant background characteristics.[17,18] The psychosocial assessment is especially important in the genetic counseling process because individuals most vulnerable to adverse effects of genetic information may include those who have had difficulty dealing with stressful life events in the past.[19] Variables that may influence psychosocial adjustment to genetic information include individual and familial factors; cultural factors; and health system factors such as the type of test, disease status, and risk information.[19] Findings from a psychosocial assessment can be used to help guide the direction of the counseling session.[9] An important objective of genetic counseling is to provide an opportunity for shared decision making when the medical benefits of one course of action are not demonstrated to be superior to another. The relationship between the availability of effective medical treatment for carriers of pathogenic variants and the clinical validity of a given test affects the degree to which personal choice or physician recommendation is supported in counseling at-risk individuals.[20] Uptake of genetic counseling services among those referred varies based on the cancer syndrome and the clinical setting. Efforts to decrease barriers to service utilization are ongoing (e.g., a patient navigator telephone call may increase utilization of these services).[21] Readers interested in the nature and history of genetic counseling are referred to a number of comprehensive reviews.[22-27]

Cancer Risk Assessment Counseling

Cancer risk assessment counseling has emerged as a specialized practice that requires knowledge of genetics, oncology, and individual and family counseling skills that may be provided by health care providers with this interdisciplinary training.[28] Some centers providing cancer risk assessment services involve a multidisciplinary team, which may include a genetic counselor; a genetics advanced practice nurse; a medical geneticist or a physician, such as an oncologist, surgeon, or internist; and a mental health professional. The Cancer Genetics Services Directory provides a partial list of individuals involved in cancer risk assessment, genetic counseling, testing, and other related services and is available on the National Cancer Institute's website.

The need for advanced professional training in cancer genetics for genetics counselors, physicians, nurses, laboratory technicians, and others has been widely reported.[29-32] Despite these identified needs, the evidence indicates that competency in genetics and genomics remains limited across all health care disciplines, with the exception of genetic specialists.[33] Deficits in the following have been identified: (1) knowledge about hereditary cancer syndromes [34] and risk-appropriate management strategies;[35] (2) provision of genetic counseling services;[35] (3) documentation and use of personal and family cancer history to identify and refer patients at increased risk of hereditary cancer syndromes;[36-39] and (4) knowledge about genetic nondiscrimination laws.[36,40] (Refer to the table on Health Professional Practice and Genetic Education Information in the PDQ Cancer Genetics Overview summary for more information.)

The National Coalition for Health Professional Education in Genetics (whose work was transitioned to The Jackson Laboratory in 2013) has published core competencies for all health professionals. Building on this work, individual health professions, such as physicians,[32] nurses,[41,42] physician assistants,[43] pharmacists,[44] and genetic counselors,[45] have developed and published core competencies specific to their profession. A number of other organizations have also published professional guidelines, scopes, and standards of practice.

Traditionally, genetic counseling services have been delivered using individualized in-person appointments. However, other methodologies are being explored, including group sessions, telephone counseling, and telemedicine by videoconferencing.[46-53] Additionally, computer programs and websites designed to provide genetics education can be successful adjuncts to personal genetic counseling services in a computer-literate population.[54-58]

Some studies of patient satisfaction with cancer genetic counseling services have been published. For example, one survey of individuals who participated in a cancer genetics program in its inaugural year reported that the clinical services met the needs and expectations of most people.[59] Patients reported that the best parts of the experience were simply having a chance to talk to someone about cancer concerns, having personalized summary letters and family pedigrees, learning that cancer risk was lower than expected, or realizing that one had been justified in suspecting the inheritance of cancer in one’s family.

Several studies have since shown that the majority of individuals are satisfied with their genetic counseling experience.[60-63] However, one study of 61 women participating in a BRCA1/2 genetic testing program found that satisfaction with genetic counseling was influenced by psychological variables including optimism, family functioning, and general and cancer-specific distress.[64]

A meta-analysis of several controlled studies showed that outcomes of genetic counseling included improvement in cancer genetic knowledge (pooled short-term difference, 0.70 U; 95% confidence interval, 0.15–1.26 U). Overall, no long-term increases in general anxiety, cancer-specific worry, distress, or depression were detected as a consequence of genetic counseling. However, the impact of genetic counseling on risk perception is less clear, with some studies reporting no change in risk perception while others report significant differences before and after counseling.[65]

References
  1. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
  2. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
  3. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
  4. Botkin JR, Belmont JW, Berg JS, et al.: Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents. Am J Hum Genet 97 (1): 6-21, 2015. [PUBMED Abstract]
  5. Statement of the American Society of Human Genetics on genetic testing for breast and ovarian cancer predisposition. Am J Hum Genet 55 (5): i-iv, 1994. [PUBMED Abstract]
  6. International Society of Nurses in Genetics: Provision of Quality Genetic Services and Care: Building a Multidisciplinary, Collaborative Approach among Genetic Nurses and Genetic Counselors. Pittsburgh, Pa: International Society of Nurses in Genetics, 2006. Available online. Last accessed March 10, 2016.
  7. International Society of Nurses in Genetics: Genetic Counseling for Vulnerable Populations: The Role of Nursing. Pittsburgh, Pa: International Society of Nurses in Genetics, 2010. Available online. Last accessed March 10, 2016.
  8. Resta R, Biesecker BB, Bennett RL, et al.: A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns 15 (2): 77-83, 2006. [PUBMED Abstract]
  9. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
  10. Berliner JL, Fay AM, Cummings SA, et al.: NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 22 (2): 155-63, 2013. [PUBMED Abstract]
  11. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2016. Fort Washington, PA: National Comprehensive Cancer Network, 2016. Available online with free registration. Last accessed October 6, 2016.
  12. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2015. Fort Washington, PA: National Comprehensive Cancer Network, 2015. Available online with free registration. Last accessed October 6, 2016.
  13. Oncology Nursing Society: Oncology Nursing: The Application of Cancer Genetics and Genomics Throughout the Oncology Care Continuum. Pittsburgh, Pa: Oncology Nursing Society, 2016. Available online. Last accessed March 10, 2016.
  14. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
  15. Resta RG: Defining and redefining the scope and goals of genetic counseling. Am J Med Genet C Semin Med Genet 142C (4): 269-75, 2006. [PUBMED Abstract]
  16. Genetic counseling. Am J Hum Genet 27 (2): 240-2, 1975. [PUBMED Abstract]
  17. Baty BJ, Kinney AY, Ellis SM: Developing culturally sensitive cancer genetics communication aids for African Americans. Am J Med Genet 118A (2): 146-55, 2003. [PUBMED Abstract]
  18. Jenkins JF, Lea DH: Nursing Care in the Genomic Era: A Case-Based Approach. Sudbury, Mass: Jones and Bartlett Publishers, 2005.
  19. Meiser B, Gaff C, Julian-Reynier C, et al.: International perspectives on genetic counseling and testing for breast cancer risk. Breast Dis 27: 109-25, 2006-2007. [PUBMED Abstract]
  20. Burke W, Pinsky LE, Press NA: Categorizing genetic tests to identify their ethical, legal, and social implications. Am J Med Genet 106 (3): 233-40, 2001 Fall. [PUBMED Abstract]
  21. Rahm AK, Sukhanova A, Ellis J, et al.: Increasing utilization of cancer genetic counseling services using a patient navigator model. J Genet Couns 16 (2): 171-7, 2007. [PUBMED Abstract]
  22. Walker AP: The practice of genetic counseling. In: Baker DL, Schuette JL, Uhlmann WR, eds.: A Guide to Genetic Counseling. New York, NY: Wiley-Liss, 1998, pp 1-26.
  23. Bartels DM, LeRoy BS, Caplan AL, eds.: Prescribing Our Future: Ethical Challenges in Genetic Counseling. New York, NY: Aldine De Gruyter, 1993.
  24. Kenen RH: Genetic counseling: the development of a new interdisciplinary occupational field. Soc Sci Med 18 (7): 541-9, 1984. [PUBMED Abstract]
  25. Kenen RH, Smith AC: Genetic counseling for the next 25 years: models for the future. J Genet Couns 4 (2): 115-24, 1995.
  26. Biesecker BB: Goals of genetic counseling. Clin Genet 60 (5): 323-30, 2001. [PUBMED Abstract]
  27. Weil Jon: Psychosocial Genetic Counseling. New York, NY: Oxford University Press, 2000.
  28. Freedman AN, Wideroff L, Olson L, et al.: US physicians' attitudes toward genetic testing for cancer susceptibility. Am J Med Genet A 120A (1): 63-71, 2003. [PUBMED Abstract]
  29. Holtzman NA, Watson MS, eds.: Promoting Safe and Effective Genetic Testing in the United States: Final Report of the Task Force on Genetic Testing. Baltimore, Md: Johns Hopkins Press, 1998. Also available online. Last accessed April 21, 2016.
  30. McInerney JD: Genetics education for health professionals: a context. J Genet Couns 17 (2): 145-51, 2008. [PUBMED Abstract]
  31. Marzuillo C, De Vito C, Boccia S, et al.: Knowledge, attitudes and behavior of physicians regarding predictive genetic tests for breast and colorectal cancer. Prev Med 57 (5): 477-82, 2013. [PUBMED Abstract]
  32. Korf BR, Berry AB, Limson M, et al.: Framework for development of physician competencies in genomic medicine: report of the Competencies Working Group of the Inter-Society Coordinating Committee for Physician Education in Genomics. Genet Med 16 (11): 804-9, 2014. [PUBMED Abstract]
  33. Harvey EK, Fogel CE, Peyrot M, et al.: Providers' knowledge of genetics: A survey of 5915 individuals and families with genetic conditions. Genet Med 9 (5): 259-67, 2007. [PUBMED Abstract]
  34. Wideroff L, Vadaparampil ST, Greene MH, et al.: Hereditary breast/ovarian and colorectal cancer genetics knowledge in a national sample of US physicians. J Med Genet 42 (10): 749-55, 2005. [PUBMED Abstract]
  35. Pal T, Cragun D, Lewis C, et al.: A statewide survey of practitioners to assess knowledge and clinical practices regarding hereditary breast and ovarian cancer. Genet Test Mol Biomarkers 17 (5): 367-75, 2013. [PUBMED Abstract]
  36. Lowstuter KJ, Sand S, Blazer KR, et al.: Influence of genetic discrimination perceptions and knowledge on cancer genetics referral practice among clinicians. Genet Med 10 (9): 691-8, 2008. [PUBMED Abstract]
  37. Meyer LA, Anderson ME, Lacour RA, et al.: Evaluating women with ovarian cancer for BRCA1 and BRCA2 mutations: missed opportunities. Obstet Gynecol 115 (5): 945-52, 2010. [PUBMED Abstract]
  38. Bellcross CA, Leadbetter S, Alford SH, et al.: Prevalence and healthcare actions of women in a large health system with a family history meeting the 2005 USPSTF recommendation for BRCA genetic counseling referral. Cancer Epidemiol Biomarkers Prev 22 (4): 728-35, 2013. [PUBMED Abstract]
  39. Wood ME, Kadlubek P, Pham TH, et al.: Quality of cancer family history and referral for genetic counseling and testing among oncology practices: a pilot test of quality measures as part of the American Society of Clinical Oncology Quality Oncology Practice Initiative. J Clin Oncol 32 (8): 824-9, 2014. [PUBMED Abstract]
  40. Laedtke AL, O'Neill SM, Rubinstein WS, et al.: Family physicians' awareness and knowledge of the Genetic Information Non-Discrimination Act (GINA). J Genet Couns 21 (2): 345-52, 2012. [PUBMED Abstract]
  41. Jenkins J, Calzone KA: Establishing the essential nursing competencies for genetics and genomics. J Nurs Scholarsh 39 (1): 10-6, 2007. [PUBMED Abstract]
  42. Greco KE, Tinley S, Seibert D: Development of the essential genetic and genomic competencies for nurses with graduate degrees. Annu Rev Nurs Res 29: 173-90, 2011. [PUBMED Abstract]
  43. Rackover M: Establishing essential physician assistant clinical competencies guidelines for genetics and genomics. The Journal of Physician Assistant Education 18 (2): 47-8, 2007.
  44. Genetics/Genomics Competency Center (G2C2): History of the Pharmacist Competencies in Pharmacogenomics. Bethesda, Md: Genetics/Genomics Competency Center, 2012. Available online. Last accessed April 21, 2016.
  45. National Society of Genetic Counselors: Core Skills of Genetic Counselors. Chicago, Ill: National Society of Genetic Counselors, 2008. Available online. Last accessed April 21, 2016.
  46. Ormond K: Recommendations for telephone counseling. J Genet Couns 9 (1): 63-71, 2000.
  47. Sangha K: Assessment of the effectiveness of genetic counseling by telephone compared to a clinic visit. J Genet Couns 12 (2): 171-84, 2003.
  48. Calzone KA, Prindiville SA, Jourkiv O, et al.: Randomized comparison of group versus individual genetic education and counseling for familial breast and/or ovarian cancer. J Clin Oncol 23 (15): 3455-64, 2005. [PUBMED Abstract]
  49. Jenkins J, Calzone KA, Dimond E, et al.: Randomized comparison of phone versus in-person BRCA1/2 predisposition genetic test result disclosure counseling. Genet Med 9 (8): 487-95, 2007. [PUBMED Abstract]
  50. Peshkin BN, Demarco TA, Graves KD, et al.: Telephone genetic counseling for high-risk women undergoing BRCA1 and BRCA2 testing: rationale and development of a randomized controlled trial. Genet Test 12 (1): 37-52, 2008. [PUBMED Abstract]
  51. Zilliacus EM, Meiser B, Lobb EA, et al.: Women's experience of telehealth cancer genetic counseling. J Genet Couns 19 (5): 463-72, 2010. [PUBMED Abstract]
  52. Rothwell E, Kohlmann W, Jasperson K, et al.: Patient outcomes associated with group and individual genetic counseling formats. Fam Cancer 11 (1): 97-106, 2012. [PUBMED Abstract]
  53. Platten U, Rantala J, Lindblom A, et al.: The use of telephone in genetic counseling versus in-person counseling: a randomized study on counselees' outcome. Fam Cancer 11 (3): 371-9, 2012. [PUBMED Abstract]
  54. Green MJ, Biesecker BB, McInerney AM, et al.: An interactive computer program can effectively educate patients about genetic testing for breast cancer susceptibility. Am J Med Genet 103 (1): 16-23, 2001. [PUBMED Abstract]
  55. Green MJ, McInerney AM, Biesecker BB, et al.: Education about genetic testing for breast cancer susceptibility: patient preferences for a computer program or genetic counselor. Am J Med Genet 103 (1): 24-31, 2001. [PUBMED Abstract]
  56. Wang C, Gonzalez R, Milliron KJ, et al.: Genetic counseling for BRCA1/2: a randomized controlled trial of two strategies to facilitate the education and counseling process. Am J Med Genet A 134 (1): 66-73, 2005. [PUBMED Abstract]
  57. Joseph G, Beattie MS, Lee R, et al.: Pre-counseling education for low literacy women at risk of Hereditary Breast and Ovarian Cancer (HBOC): patient experiences using the Cancer Risk Education Intervention Tool (CREdIT). J Genet Couns 19 (5): 447-62, 2010. [PUBMED Abstract]
  58. Albada A, van Dulmen S, Lindhout D, et al.: A pre-visit tailored website enhances counselees' realistic expectations and knowledge and fulfils information needs for breast cancer genetic counselling. Fam Cancer 11 (1): 85-95, 2012. [PUBMED Abstract]
  59. Stadler MP, Mulvihill JJ: Cancer risk assessment and genetic counseling in an academic medical center: consultands' satisfaction, knowledge, and behavior in the first year. J Genet Couns 7 (3): 279-97, 1998.
  60. Chen WY, Garber JE, Higham S, et al.: BRCA1/2 genetic testing in the community setting. J Clin Oncol 20 (22): 4485-92, 2002. [PUBMED Abstract]
  61. Nordin K, Lidén A, Hansson M, et al.: Coping style, psychological distress, risk perception, and satisfaction in subjects attending genetic counselling for hereditary cancer. J Med Genet 39 (9): 689-94, 2002. [PUBMED Abstract]
  62. Klemp JR, O'Dea A, Chamberlain C, et al.: Patient satisfaction of BRCA1/2 genetic testing by women at high risk for breast cancer participating in a prevention trial. Fam Cancer 4 (4): 279-84, 2005. [PUBMED Abstract]
  63. Bober SL, Hoke LA, Duda RB, et al.: Recommendation recall and satisfaction after attending breast/ovarian cancer risk counseling. J Genet Couns 16 (6): 755-62, 2007. [PUBMED Abstract]
  64. Tercyak KP, Demarco TA, Mars BD, et al.: Women's satisfaction with genetic counseling for hereditary breast-ovarian cancer: psychological aspects. Am J Med Genet A 131 (1): 36-41, 2004. [PUBMED Abstract]
  65. Braithwaite D, Emery J, Walter F, et al.: Psychological impact of genetic counseling for familial cancer: a systematic review and meta-analysis. J Natl Cancer Inst 96 (2): 122-33, 2004. [PUBMED Abstract]

Components of the Risk Assessment Process

This section provides an overview of critical elements in the cancer risk assessment process.

A number of professional guidelines on the elements of cancer genetics risk assessment and counseling are available.[1-4] Except where noted, the discussion below is based on these guidelines.

The cancer risk assessment and counseling process, which may vary among providers, requires one or more consultative sessions and generally includes the following:

  • A detailed, multifaceted assessment including family history.
  • A determination of the risk of cancer and/or indication for genetic testing based on evidence of an inherited cancer syndrome.
  • Education and counseling.
  • Review of genetic testing options.
  • Establishment of a cancer risk management plan.

Assessment

At the outset of the initial counseling session, eliciting and addressing the consultand's perceptions and concerns about cancer and his or her expectations of the risk assessment process helps to engage the consultand in the session. This also helps inform the provider about practical or psychosocial issues and guides the focus of counseling and strategies for risk assessment.

Psychosocial assessment

The counseling process that takes place as part of a cancer risk assessment can identify factors that contribute to the consultand's perception of cancer risk and motivations to seek cancer risk assessment and genetic testing. It can also identify potential psychological issues that may need to be addressed during or beyond the session. Information collected before and/or during the session may include the following:

  • Motivations for seeking cancer risk assessment.
  • Beliefs about the causes of cancer.
  • Experiences with cancer and feelings, perceptions, concerns, or fears related to those experiences.
  • The influence of cancer experiences and perceptions on health behaviors and cancer screening practices.
  • Cultural, religious, and socioeconomic background.
  • General psychological issues, such as depression or anxiety.
  • Coping mechanisms.
  • Support systems.

Either alone or in consultation with a mental health provider, health care providers offering cancer risk counseling attempt to assess whether the individual's expectations of counseling are realistic and whether there are factors suggesting risk of adverse psychological outcomes after disclosure of risk and/or genetic status. In some cases, referral for psychotherapeutic treatment may be recommended prior to, or in lieu of, testing.[5]

Education

Concepts of personal cancer risk, genetics, and the relationship between the two can be complex and can be difficult for patients to understand. A number of factors influence a person’s concept of his or her risk, which may not be congruent with evidence-based quantitative calculations. These factors include:

  • Experiential and empathetic knowledge.
  • People's beliefs regarding the basis for the occurrence of cancer in themselves and/or their relatives.
  • Sources of information and inaccuracies and/or misperceptions.
  • Literacy level, including health and numeracy.[6,7]
  • Personal theories of inheritance.
  • Patterns of decision making (deliberate vs. experiential).[8,9]

A thorough understanding of these issues can greatly inform genetic education and counseling. These factors influence the processing of risk information and subsequent health behaviors.[9]

Risk perception

The communication of risk involves the delivery of quantitative information regarding what the data indicate about the likelihood of developing illness given various preventive actions. More broadly, however, risk communication is an interactive process regarding the individual’s knowledge, beliefs, emotions, and behaviors associated with risk and the risk message conveyed. Accordingly, the goal of risk communication may be to impact the individual’s knowledge of risk factors, risk likelihoods, potential consequences of risk, and the benefits and drawbacks of preventive actions.

Even before the provision of risk information, the provider may anticipate that the individual already has some sense of his or her own risk of cancer. The individual may have derived this information from multiple sources, including physicians, family members, and the media.[10] This information may be more salient or emotional if a family member has recently died from cancer or if there is a new family diagnosis.[11,12] Additionally, individuals may have beliefs about how genetic susceptibility works in their family.[13,14] For example, in a family where only females have been affected with an autosomal dominant cancer susceptibility syndrome thus far, it may be difficult to convince the consultand that her sons have a 50% risk of inheriting the disease-related pathogenic variant. The social-ecological context through which risk beliefs develop and are maintained are important as potential moderators of individuals’ receptivity to the cancer risk communication process and also represent the context in which individuals will return to continue ongoing decision making about how to manage their risk.[15,16] As such, individuals’ beliefs, and the social context of risk, are important to discuss in education and genetic risk counseling.

Perceived risk can play an important role in an individual’s decision to participate in counseling,[17] despite the fact that perceived risk often varies substantially from statistical risk estimates.[18-20]

Clinical Evaluation

Personal health history

Consideration of the consultand's personal health history is essential in cancer risk assessment, regardless of whether the individual has a personal history of cancer. Important information to obtain about the consultand's health history includes the following:

  • Current age.
  • Race and ethnicity.
  • History of benign or malignant tumors, surgeries, biopsies, major illnesses, medications, and reproductive history (for women, this includes age at menarche, parity, age at first live birth, age at menopause, and history of exogenous hormone use).
  • Environmental exposures.
  • Diet and exercise practices.
  • Complementary and alternative medicine practices.
  • Past and current alcohol intake and tobacco use.
  • Screening practices and date of last screening exams, including imaging and/or physical examinations.[1,3,21]

For consultands with a history of cancer, additional information collected includes the following:

  • Site of primary tumor.
  • Age at diagnosis.
  • Tumor pathology.
  • Treatment (e.g., surgery, chemotherapy, and radiation therapy).
  • Bilaterality of disease, if applicable.
  • Current surveillance plan.[1]

Physical examination

In some cases, a physical exam is conducted by a qualified medical professional to determine whether the individual has physical findings suggestive of a hereditary cancer predisposition syndrome or to rule out evidence of an existing malignancy. For example, a medical professional may look for the sebaceous adenomas seen in Muir-Torre syndrome, measure the head circumference or perform a skin exam to rule out benign cutaneous features associated with Cowden syndrome, or perform a clinical breast and axillary lymph node exam on a woman undergoing a breast cancer risk assessment.

Family history

Documenting the family history

The family history is an essential tool for cancer risk assessment. The family history can be obtained via interview or written self-report; both were found to result in equivalent information in a study that utilized a sample (N = 104) that varied widely in educational attainment.[22] A nine-question family history screening tool has been shown to identify individuals at increased risk of common health conditions, including cancer, who warrant a more detailed family history (receiver operating characteristic, 84.6% [range, 81.2%–88.1%]; sensitivity, 95% [range, 92%–98%]; specificity, 54% [range, 48%–60%]).[23] Studies suggest that paper-based family history questionnaires completed before the appointment provide accurate family history information [24] and that the use of these questionnaires is an acceptable and understandable family history collection method.[25] However, questionnaire-based assessments may lead to some underreporting of family history; therefore, a follow-up interview to confirm the reported information and to capture all relevant family history information may be required.[26] Routine chart reviews (e.g., via electronic medical records) may be worthwhile to maximize the identification of appropriate candidates for genetic counseling referral. In a single nonacademic institution, systematic chart review by a genetic counselor increased the number of referrals for genetics consultation.[27] The most significant improvement was in ovarian cancer referrals. In conjunction with other efforts to collect and review family history, the performance of routine chart reviews may help identify gaps in existing referral patterns. Additionally, collecting family history from multiple relatives in a single family has been shown to increase the number of reported family members with cancer, compared with family history information provided by a single family member.[28]

Details of the family health history are best summarized in the form of a family tree, or pedigree. The pedigree, a standardized graphic representation of family relationships, facilitates identification of patterns of disease transmission, recognition of the clinical characteristics associated with specific hereditary cancer syndromes, and determination of the best strategies and tools for risk assessment.[29,30] Factors suggesting inherited cancer risk in a family are described below.

Both multimedia-based (e.g., Internet) and print-based (e.g., family history questionnaires) tools are currently available to gather information about family history. In the United States, many are written at reading grade levels above 8th grade, which may reduce their effectiveness in gathering accurate family history information. On average, print-based tools have been found to be written at lower reading grade levels than multimedia-based tools.[31]

Standards of pedigree nomenclature have been established.[29,30] Refer to Figure 1 for common pedigree symbols.

Enlarge Standard pedigree nomenclature; diagram shows common symbols used to draw a pedigree.
Figure 1. Standard pedigree nomenclature. Common symbols are used to draw a pedigree (family tree). A pedigree shows relationships between family members and patterns of inheritance for certain traits and diseases.

Documentation of a family cancer history typically includes the following:

  • A minimum of first- and second-degree relatives on both the maternal and paternal sides of the family. Information on multiple generations helps to demonstrate inheritance patterns. Hereditary cancer can be inherited from either the maternal or paternal side of the family and is often an adult-onset disease.[32]
  • Race, ancestry, and ethnicity of all grandparents. This may influence decisions about genetic testing because specific pathogenic variants in some genes are known to occur with increased frequency in some populations (founder effect).[32]
  • Information about seemingly unrelated conditions, such as birth defects, atypical skin bumps, or other nonmalignant conditions of children and adults that may aid in the diagnosis of a cancer susceptibility syndrome.
  • Notation of adoption, nonpaternity (the biologic father should be included in the pedigree), consanguinity, and use of assisted reproductive technology (e.g., donor egg or sperm), when available.

A three-generation family history includes the following:

  • First-degree relatives (e.g., children, brothers and sisters, and parents).
  • Second-degree relatives (e.g., grandparents, aunts and uncles, nieces and nephews, grandchildren, and half-siblings).
  • Third-degree relatives (e.g., first cousins, great aunts, and great uncles).
  • Additional distant relatives are included if information is available, especially when there are known cancer histories among them.

For any relative with cancer, collect the following information:[33]

  • Primary site of each cancer, with supportive documentation of key cancers (if available) to confirm primary site and histology (e.g., pathology reports, clinical documents, and death certificates).
  • Age at diagnosis for each primary cancer.
  • Where the relative was diagnosed and/or treated.
  • History of surgery or treatments that may have reduced the risk of cancer. For example, bilateral salpingo-oophorectomy in a premenopausal woman significantly reduces the risk of ovarian and breast cancers. This may mask underlying hereditary predisposition to these cancers.
  • Current age (if living).
  • Age at death and cause of death (if deceased).
  • Carcinogenic exposures (e.g., tobacco use and radiation exposure).
  • Other significant health problems.

For relatives not affected with cancer, collect the following information:

  • Current age or age at death.
  • Cause of death (if deceased).
  • History of any surgeries or treatments that may have reduced the risk of cancer.
  • Cancer screening practices.
  • Any nonmalignant features associated with the syndrome in question.
  • Carcinogenic exposures.
  • Other significant health problems.
Accuracy of the family history

The accuracy of the family history has a direct bearing on determining the differential diagnoses, selecting appropriate testing, interpreting results of the genetic tests, refining individual cancer risk estimates, and outlining screening and risk reduction recommendations. In a telephone survey of 1,019 individuals, only 6% did not know whether a first-degree relative had cancer; this increased to 8.5% for second-degree relatives.[34] However, people often have incomplete or inaccurate information about the cancer history in their family.[30,33,35-41] Patient education has been shown to improve the completeness of family history collection and may lead to more-accurate risk stratification, referrals for genetic counseling, and changes to management recommendations.[42] Confirming the primary site of cancers in the family that will affect the calculation of hereditary predisposition probabilities and/or estimation of empiric cancer risks may be important, especially if decisions about treatments such as risk-reducing surgery will be based on this family history.[37,43]

A population-based survey of 2,605 first- and second-degree relatives confirmed proband reports of cancer diagnoses and found that the accuracy of reported cancer diagnoses in relatives was low to moderate, while reports of no history of cancer were accurate.[39] Accuracy varies by cancer site and degree of relatedness.[39,44,45] Reporting of cancer family histories may be most accurate for breast cancer [39,45] and less accurate for gynecologic malignancies [39,45] and colon cancer.[39] Self-reported family histories may contain errors and, in rare instances, could be fictitious.[37,43,45] The most reliable documentation of cancer histology is the pathology report. Verification of cancers can also be made through other medical records, tumor registries, or death certificates. A U.K. study illustrates the importance of verification of the cancer family history in individuals with a family history of breast cancer (n = 2,278) and colon cancer (n = 1,184).[41] Changes in genetic risk assignment (reassignment) from baseline to final time points (e.g., low risk to high risk) warranting management changes were reported in nearly 30% of families with colorectal cancer and 20% of families with breast cancer. Verification of reported cancer diagnoses in this cohort revealed a lower overall degree of consistency between reported and confirmed diagnoses than in other studies.[37,46]

It is also important to consider limited, missing, or questionable information when reviewing a pedigree for cancer risk assessment. It is more difficult to identify features of hereditary disease in families with a truncated family structure due to loss of contact with relatives, small family size, or deaths at an early age from unrelated conditions. When there are few family members of the at-risk gender when considering a particular syndrome with primarily male or female specific disease manifestations, the family history may be difficult to assess (e.g., few female members in a family at risk of hereditary breast and ovarian cancer syndrome). In addition, information collected on risk-reducing surgical procedures, such as oophorectomy, could significantly change prior probability estimation and the constellation of cancers observed in a family.[47] Other factors to clarify and document whenever possible are adoptions, use of donor egg or sperm, consanguinity, and uncertain paternity.

Additionally, family histories are dynamic. The occurrence of additional cancers may alter the likelihood of a hereditary predisposition to cancer, and consideration of differential diagnoses or empiric cancer risk estimates may change if additional cancers arise in the family. Furthermore, changes in the cancer family history over time may alter recommendations for earlier or more intense cancer screening. A descriptive study that examined baseline and follow-up family history data from a U.S. population-based cancer registry reported that family history of breast cancer or colorectal cancer becomes increasingly relevant in early adulthood and changes significantly from age 30 years to age 50 years.[48] Therefore, it is important to advise the consultand to take note of, confirm, and report cancer diagnoses or other pertinent family health history that occurs after completion of the initial risk assessment process. This is especially important if genetic testing was not performed or was uninformative.

Finally, the process of taking the family history has a psychosocial dimension. Discussing and documenting discrete aspects of family relationships and health brings the family into the session symbolically, even when a single person is being counseled. Problems that may be encountered in eliciting a family history and constructing a pedigree include difficulty contacting relatives with whom one has little or no relationship, differing views between family members about the value of genetic information, resistance to discussion of cancer and cancer-related illness, unanticipated discovery of previously unknown medical or family information, and coercion of one relative by another regarding testing decisions. In addition, unexpected emotional distress may be experienced by the consultand in the process of gathering family history information.

Indications for referral to cancer risk assessment and counseling

After an individual’s personal and family cancer histories have been collected, several factors could warrant referral to a genetics professional for evaluation of hereditary cancer susceptibility syndromes. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors have published a comprehensive set of personal and family history criteria to guide the identification of at-risk individuals and appropriate referral for cancer genetic risk consultation.[49] These practice guidelines take into account tumor types or other features and related criteria that would indicate a need for a genetics referral. The authors state that the guidelines are intended to maximize appropriate referral of at-risk individuals for cancer genetic consultation but are not meant to provide genetic testing or treatment recommendations.

Determining Cancer Risk

Analysis of the family history

Because a family history of cancer is one of the important predictors of cancer risk, analysis of the pedigree constitutes an important aspect of risk assessment. This analysis might be thought of as a series of the following questions:

  • What is the evidence that a cancer susceptibility syndrome is present in this family?
  • If a syndrome is present, what is the most probable diagnosis?
  • What could make this family history difficult to interpret?
  • What is the most likely mode of inheritance, regardless of whether a specific syndrome diagnosis can be established?
  • What is the chance of a member of this family developing cancer, if an inherited susceptibility exists?
  • If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?

The following sections relate to the way that each of these questions might be addressed:

  1. What is the evidence that a cancer susceptibility syndrome is present in this family?

    The clues to a hereditary syndrome are based on pedigree analysis and physical findings. The index of suspicion is raised by the following:

    • Multiple cancers in close relatives, particularly in multiple generations.
    • Early age of cancer onset (younger than age 40 to 50 years for adult-onset cancers).
    • Multiple cancers in a single individual.
    • Bilateral cancer in paired organs (e.g., breast and kidney).
    • Recognition of the known association between etiologically related cancers in the family.
    • Presence of congenital anomalies or precursor lesions that are known to be associated with increased cancer risk (e.g., presence of atypical nevi and risk of malignant melanoma).
    • Recognizable Mendelian inheritance pattern.
    • Specific tumor types associated with germline pathogenic variants in cancer susceptibility genes, regardless of family history.[32]

    Clinical characteristics associated with distinctive risk ranges for different cancer genetic syndromes are summarized in the second edition of the Concise Handbook of Familial Cancer Susceptibility Syndromes.[50]

  2. If a syndrome is present, what is the most probable diagnosis?

    Hundreds of inherited conditions are associated with an increased risk of cancer. These have been summarized in texts [51-53] and a concise review.[50] Diagnostic criteria for different hereditary syndromes incorporate different features from the list above, depending on the original purpose of defining the syndrome (e.g., for gene mapping, genotype -phenotype studies, epidemiological investigations, population screening, or clinical service). Thus, a syndrome such as Lynch syndrome (also called hereditary nonpolyposis colorectal cancer [HNPCC]) can be defined for research purposes by the Amsterdam criteria as having three related individuals with colorectal cancer, with one person being a first-degree relative of the other two; spanning two generations; and including one person who was younger than age 50 years at cancer diagnosis, better known as the 3-2-1 rule. These criteria have limitations in the clinical setting, however, in that they ignore endometrial and other extracolonic tumors known to be important features of Lynch syndrome. Revised published criteria that consider extracolonic cancers of Lynch syndrome have been subsequently developed and include the Amsterdam criteria II and the revised Bethesda guidelines.

  3. What could make the family history difficult to interpret?

    Other factors may complicate recognition of basic inheritance patterns or represent different types of disease etiology. These factors include the following:

    • Small family size.
    • Gender imbalance (e.g., few women in a family suspected of hereditary breast cancer).
    • Deaths at particularly early ages.
    • Removal of the at-risk organ, either for risk reduction or as a result of a medical condition (e.g., total abdominal hysterectomy due to history of uterine fibroids or endometriosis).
    • Misidentified parentage.
    • Late or variable onset.
    • Nonpenetrance.
    • Variable expression.
    • Genetic heterogeneity.
    • Genomic imprinting.
    • De novo pathogenic variant.
    • Mosaicism (somatic or germline).
    • Mitochondrial inheritance.
    • Consanguinity.
    • Assisted reproductive technology (e.g., donor egg or sperm or in vitro fertilization).
  4. What is the most likely mode of inheritance, regardless of whether a syndrome diagnosis can be established?

    The mode of inheritance refers to the way that genetic traits are transmitted in the family. Mendel’s laws of inheritance posit that genetic factors are transmitted from parents to offspring as discrete units known as genes that are inherited independently from each other and are passed on from an older generation to the following generation. The most common forms of Mendelian inheritance are autosomal dominant, autosomal recessive, and X-linked. Non-Mendelian forms of inheritance include chromosomal, complex, and mitochondrial. Researchers have learned from cancer and other inherited diseases that even Mendelian inheritance is modified by environmental and other genetic factors and that there are variations in the ways that the laws of inheritance work.[54-56]

    Most commonly, Mendelian inheritance is established by a combination of clinical diagnosis with a compatible, but not in itself conclusive, pedigree pattern.[57] Below is a list of inheritance patterns with clues to their recognition in the pedigree, followed by a list of situations that may complicate pedigree interpretation.

    Autosomal dominant

    • Autosomal dominant inheritance refers to disorders that are expressed in the heterozygote (i.e., the affected person has one copy of a variant allele and one allele that is functioning normally). Autosomal dominant inheritance is characterized by the following:
      • Vertical occurrence (i.e., seen in successive generations).
      • Usually seen only on one side of the family (i.e., unipaternal or unimaternal).
      • Males and females may inherit and transmit the disorder to offspring.
      • Male-to-male transmission may be seen.
      • Offspring have a 50% chance of inheriting a pathogenic variant and a 50% chance of inheriting the normal allele.
      • The condition may appear to skip a generation due to incomplete penetrance, early death due to other causes, delayed age of onset, or paucity of males or females when the at-risk organ is gender-specific (e.g., prostate and ovary).
      • Most currently known cancer susceptibility syndromes follow an autosomal dominant inheritance pattern. Examples include hereditary breast and ovarian cancer syndrome, Lynch syndrome, familial adenomatous polyposis, and von Hippel Lindau disease.
      • It is possible for an individual to have a genetic variant that has not previously been expressed as an autosomal dominant family history of cancer due to a variety of factors discussed above (see question #3).
      • It is possible for an individual to have a de novo (new) pathogenic variant. This person would be the first affected member of his or her family but could transmit this trait in the usual autosomal dominant manner to their offspring.

    Autosomal recessive

    • Autosomal recessive inheritance refers to an inheritance pattern in which an affected person must be homozygous (i.e., carry two copies of a altered gene, one from each parent). Autosomal recessive inheritance is characterized by the following:
      • Horizontal occurrence (i.e., seen in one generation only [affected siblings in the absence of affected parents]); generally not seen in successive generations.
      • Genetic variants must come from both sides of the family (i.e., biparental inheritance).
      • Parents are heterozygous carriers; each carries one variant copy of the gene and one functional copy.
      • Parents usually do not express the trait or the full syndrome; in some cases, parents may show a mild version of some features.
      • Two heterozygous parents together have a 25% risk for future offspring being affected.
      • Some well-defined cancer susceptibility syndromes with an autosomal recessive inheritance pattern include Bloom syndrome, Ataxia Telangiectasia, MYH-associated polyposis, and Fanconi anemia.

    X-linked

    • X-linked inheritance refers to inheritance of genes located on the X chromosome. Because males carry one Y and one X chromosome, genes on their X chromosome are hemizygous and may be expressed, regardless of whether the trait is dominant or recessive in females. X-linked recessive inheritance is more common than X-linked dominant and is characterized by the following:
      • Male and female offspring have a 50% chance of inheriting the variant allele from a female carrier.
      • Males in the maternal lineage (brothers and maternal uncles) are affected.
      • Females are rarely affected, but when they are, the effects are usually milder than the effects in males.
      • No father-to-son transmission of the pathogenic variant occurs (i.e., a father cannot transmit an X-linked condition to his son because he gives the son his Y chromosome and not his X).
      • It is unusual for a cancer susceptibility syndrome to show X-linked transmission. One rare example is X-linked lymphoproliferative disorder.

    Chromosomal

    • Chromosomal disorders generally are not inherited conditions, except in rare cases of chromosomal translocations. Rather, they occur as a de novo error in meiosis at the time of conception of a given individual. Certain chromosomal anomalies confer a risk of malignancy; thus, inquiries about birth defects and intellectual disability are important for thorough pedigree construction and interpretation. Examples of chromosomal disorders with increased risk of malignancy include leukemia associated with Down syndrome (trisomy 21) and breast cancer associated with Klinefelter syndrome (47,XXY karyotype).

    Complex

    • Complex or multifactorial disease inheritance is used to describe conditions caused by genetic and environmental factors. Thus, a condition may be caused by the expression of multiple genes or by the interaction of genes and environmental factors. Therefore, a single genetic locus is not responsible for the condition. Rather, the net effect of genetic, lifestyle, and environmental factors determines a person’s liability to be affected with a condition, such as cancer.

      Susceptibility or resistance shows a more or less normal distribution in the population. Most people have an intermediate susceptibility, with those at the tails of the distribution curve having unusually low or unusually high susceptibility. Affected individuals are presumably those who are past a point of threshold for being affected due to their particular combination of risk factors. Outside of the few known Mendelian syndromes that predispose to a high incidence of specific cancer, most cancers are complex in etiology.

      Clustering of cancer among relatives is common, but teasing out the underlying causes when there is no clear pattern is more difficult. With many common malignancies, such as lung cancer, an excess of cancers in relatives can be seen. These familial aggregations are seen as being due to combinations of exposures to known carcinogens, such as tobacco smoke, and to pathogenic variants in high penetrance genes or alterations in genes with low penetrance that affect the metabolism of the carcinogens in question.[58]

      The general practitioner is likely to encounter some families with a strong genetic predisposition to cancer and the recognition of cancer susceptibility may have dramatic consequences for a given individual's health and management. Although pathogenic variants in major cancer susceptibility genes lead to recognizable Mendelian inheritance patterns, they are uncommon. Nonetheless, cancer susceptibility genes are estimated to contribute to the occurrence of organ-specific cancers from less than 1% to up to 15%.[59] Pathogenic variants in these genes confer high relative risk and high absolute risk. The attributable risk is low, however, because they are so rare.

      In contrast, scientists now know of polymorphisms or alterations in deoxyribonucleic acid that are very common in the general population. Each polymorphism may confer low relative and absolute risks, but collectively they may account for high attributable risk because they are so common. Development of clinically significant disease in the presence of certain genetic polymorphisms may be highly dependent on environmental exposure to a potent carcinogen. People carrying polymorphisms associated with weak disease susceptibility may constitute a target group for whom avoidance of carcinogen exposure may be highly useful in preventing full-blown disease from occurring.

      For more information about specific low-penetrance genes, please refer to the summaries on genetics of specific types of cancer.

      Complex inheritance might be considered in a pedigree showing the following:

      • Males and females affected (unless the target organ is gender-specific).
      • A few cancers, without clear-cut vertical transmission or sibship clusters.
      • No set pattern of inheritance.
      • May appear to skip generations.
  5. What is the chance of developing cancer if an inherited susceptibility exists?

    These probabilities vary by syndrome, family, gene, and pathogenic variant, with different variants in the same gene sometimes conferring different cancer risks, or the same variant being associated with different clinical manifestations in different families. These phenomena relate to issues such as penetrance and expressivity discussed elsewhere.

  6. If no recognizable syndrome is present, is there a risk of cancer based on other epidemiological risk factors?

    A positive family history may sometimes provide risk information in the absence of a specific genetically determined cancer syndrome. For example, the risk associated with having a single affected relative with breast or colorectal cancer can be estimated from data derived from epidemiologic and family studies. Examples of empiric risk estimates of this kind are provided in the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer.

Methods of quantifying cancer risk

The overarching goal of cancer risk assessment is to individualize cancer risk management recommendations based on personalized risk. Methods to calculate risk utilize health history information and risk factor and family history data often in combination with emerging biologic and genetic/genomic evidence to establish predictions.[60] Multiple methodologies are used to calculate risk, including statistical models, prevalence data from specific populations, penetrance data when a documented pathogenic variant has been identified in a family, Mendelian inheritance, and Bayesian analysis. All models have distinct capabilities, weaknesses, and limitations based on the methodology, sample size, and/or population used to create the model. Methods to individually quantify risk encompass two primary areas: the probability of harboring a pathogenic variant in a cancer susceptibility gene and the risk of developing a specific form of cancer.[60]

Risk of harboring a pathogenic variant in a cancer susceptibility gene

The decision to offer genetic testing for cancer susceptibility is complex and can be aided in part by objectively assessing an individual's and/or family's probability of harboring a pathogenic variant.[61] Predicting the probability of harboring a pathogenic variant in a cancer susceptibility gene can be done using several strategies, including empiric data, statistical models, population prevalence data, Mendel’s laws, Bayesian analysis, and specific health information, such as tumor-specific features.[61,62] All of these methods are gene specific or cancer-syndrome specific and are employed only after a thorough assessment has been completed and genetic differential diagnoses have been established.

If a gene or hereditary cancer syndrome is suspected, models specific to that disorder can be used to determine whether genetic testing may be informative. (Refer to the PDQ summaries on the Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; or the Genetics of Skin Cancer for more information about cancer syndrome-specific probability models.) The key to using specific models or prevalence data is to apply the model or statistics only in the population best suited for its use. For instance, a model or prevalence data derived from a population study of individuals older than 35 years may not accurately be applied in a population aged 35 years and younger. Care must be taken when interpreting the data obtained from various risk models because they differ with regard to what is actually being estimated. Some models estimate the risk of a pathogenic variant being present in the family; others estimate the risk of a pathogenic variant being present in the individual being counseled. Some models estimate the risk of specific cancers developing in an individual, while others estimate more than one of the data above. (Refer to NCI's Risk Prediction Models website or the disease-specific PDQ cancer genetics summaries for more information about specific cancer risk prediction and pathogenic variant probability models.) Other important considerations include critical family constructs, which can significantly impact model reliability, such as small family size or male-dominated families when the cancer risks are predominately female in origin, adoption, and early deaths from other causes.[62,63] In addition, most models provide gene and/or syndrome-specific probabilities but do not account for the possibility that the personal and/or family history of cancer may be conferred by an as-yet-unidentified cancer susceptibility gene.[64] In the absence of a documented pathogenic variant in the family, critical assessment of the personal and family history is essential in determining the usefulness and limitations of probability estimates used to aid in the decisions regarding indications for genetic testing.[61,62,64]

When a pathogenic variant has been identified in a family and a test report documents that finding, prior probabilities can be ascertained with a greater degree of reliability. In this setting, probabilities can be calculated based on the pattern of inheritance associated with the gene in which the pathogenic variant has been identified. In addition, critical to the application of Mendelian inheritance is the consideration of integrating Bayes Theorem, which incorporates other variables, such as current age, into the calculation for a more accurate posterior probability.[1,65] This is especially useful in individuals who have lived to be older than the age at which cancer is likely to develop based on the pathogenic variant identified in their family and therefore have a lower likelihood of harboring the family pathogenic variant when compared with the probability based on their relationship to the carrier in the family.

Even in the case of a documented pathogenic variant on one side of the family, careful assessment and evaluation of the individual’s personal and family history of cancer is essential to rule out cancer risk or suspicion of a cancer susceptibility gene pathogenic variant on the other side of the family (maternal or paternal, as applicable).[66] Segregation of more than one pathogenic variant in a family is possible (e.g., in circumstances in which a cancer syndrome has founder pathogenic variants associated with families of particular ancestral origin).

Risk of developing cancer

Unlike pathogenic variant probability models that predict the likelihood that a given personal and/or family history of cancer could be associated with a pathogenic variant in a specific gene(s), other methods and models can be used to estimate the risk of developing cancer over time. Similar to pathogenic variant probability assessments, cancer risk calculations are also complex and necessitate a detailed health history and family history. In the presence of a documented pathogenic variant, cancer risk estimates can be derived from peer-reviewed penetrance data.[1] Penetrance data are constantly being refined and many genetic variants have variable penetrance because other variables may impact the absolute risk of cancer in any given patient. Modifiers of cancer risk in carriers of pathogenic variants include the variant's effect on the function of the gene/protein (e.g., variant type and position), the contributions of modifier genes, and personal and environmental factors (e.g., the impact of bilateral salpingo-oophorectomy performed for other indications in a woman who harbors a BRCA pathogenic variant).[67] When there is evidence of an inherited susceptibility to cancer but genetic testing has not been performed, analysis of the pedigree can be used to estimate cancer risk. This type of calculation uses the probability the individual harbors a genetic variant and variant-specific penetrance data to calculate cancer risk.[1]

In the absence of evidence of a hereditary cancer syndrome, several methods can be utilized to estimate cancer risk. Relative risk data from studies of specific risk factors provide ratios of observed versus expected cancers associated with a given risk factor. However, utilizing relative risk data for individualized risk assessment can have significant limitations: relative risk calculations will differ based on the type of control group and other study-associated biases, and comparability across studies can vary widely.[65] In addition, relative risks are lifetime ratios and do not provide age-specific calculations, nor can the relative risk be multiplied by population risk to provide an individual's risk estimate.[65,68]

In spite of these limitations, disease-specific cumulative risk estimates are most often employed in clinical settings. These estimates usually provide risk for a given time interval and can be anchored to cumulative risks of other health conditions in a given population (e.g., the 5-year risk by the Gail model).[65,68] Cumulative risk models have limitations that may underestimate or overestimate risk. For example, the Gail model excludes paternal family histories of breast cancer.[62] Furthermore, many of these models were constructed from data derived from predominately Caucasian populations and may have limited validity when used to estimate risk in other ethnicities.[69]

Cumulative risk estimates are best used when evidence of other underlying significant risk factors have been ruled out. Careful evaluation of an individual's personal health and family history can identify other confounding risk factors that may outweigh a risk estimate derived from a cumulative risk model. For example, a woman with a prior biopsy showing lobular carcinoma in situ (LCIS) whose mother was diagnosed with breast cancer at age 65 years has a greater lifetime risk from her history of LCIS than her cumulative lifetime risk of breast cancer based on one first-degree relative.[70,71] In this circumstance, recommendations for cancer risk management would be based on the risk associated with her LCIS. Unfortunately, there is no reliable method for combining all of an individual's relevant risk factors for an accurate absolute cancer risk estimate, nor are individual risk factors additive.

In summary, careful ascertainment and review of personal health and cancer family history are essential adjuncts to the use of prior probability models and cancer risk assessment models to assure that critical elements influencing risk calculations are considered.[61] Influencing factors include the following:

  • Differential diagnosis that is consistent with the personal and cancer family history.
  • Consideration of factors that influence how informative the family history may be.
  • Population that is best suited for the use of the model.
  • Tumor-specific features that may be suspicious for an inherited predisposition or modify individual cancer risk predictions.
  • Model-specific limitations that can overestimate or underestimate calculations.[64]

A number of investigators are developing health care provider decision support tools such as the Genetic Risk Assessment on the Internet with Decision Support (GRAIDS),[72] but at this time, clinical judgment remains a key component of any prior probability or absolute cancer risk estimation.[61]

References
  1. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
  2. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
  3. Berliner JL, Fay AM, Cummings SA, et al.: NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 22 (2): 155-63, 2013. [PUBMED Abstract]
  4. Lancaster JM, Powell CB, Chen LM, et al.: Society of Gynecologic Oncology statement on risk assessment for inherited gynecologic cancer predispositions. Gynecol Oncol 136 (1): 3-7, 2015. [PUBMED Abstract]
  5. Baum A, Friedman AL, Zakowski SG: Stress and genetic testing for disease risk. Health Psychol 16 (1): 8-19, 1997. [PUBMED Abstract]
  6. Roter DL, Erby L, Larson S, et al.: Oral literacy demand of prenatal genetic counseling dialogue: Predictors of learning. Patient Educ Couns 75 (3): 392-7, 2009. [PUBMED Abstract]
  7. Lea DH, Kaphingst KA, Bowen D, et al.: Communicating genetic and genomic information: health literacy and numeracy considerations. Public Health Genomics 14 (4-5): 279-89, 2011. [PUBMED Abstract]
  8. Pilarski R: Risk perception among women at risk for hereditary breast and ovarian cancer. J Genet Couns 18 (4): 303-12, 2009. [PUBMED Abstract]
  9. Sivell S, Elwyn G, Gaff CL, et al.: How risk is perceived, constructed and interpreted by clients in clinical genetics, and the effects on decision making: systematic review. J Genet Couns 17 (1): 30-63, 2008. [PUBMED Abstract]
  10. Street RL Jr: Mediated consumer-provider communication in cancer care: the empowering potential of new technologies. Patient Educ Couns 50 (1): 99-104, 2003. [PUBMED Abstract]
  11. Walter FM, Emery J, Braithwaite D, et al.: Lay understanding of familial risk of common chronic diseases: a systematic review and synthesis of qualitative research. Ann Fam Med 2 (6): 583-94, 2004 Nov-Dec. [PUBMED Abstract]
  12. McAllister M: Predictive genetic testing and beyond: a theory of engagement. J Health Psychol 7 (5): 491-508, 2002. [PUBMED Abstract]
  13. Henderson BJ, Maguire BT: Three lay mental models of disease inheritance. Soc Sci Med 50 (2): 293-301, 2000. [PUBMED Abstract]
  14. Richards M, Ponder M: Lay understanding of genetics: a test of a hypothesis. J Med Genet 33 (12): 1032-6, 1996. [PUBMED Abstract]
  15. Price MA, Butow PN, Lo SK, et al.: Predictors of cancer worry in unaffected women from high risk breast cancer families: risk perception is not the primary issue. J Genet Couns 16 (5): 635-44, 2007. [PUBMED Abstract]
  16. Hay JL, Meischke HW, Bowen DJ, et al.: Anticipating dissemination of cancer genomics in public health: a theoretical approach to psychosocial and behavioral challenges. Ann Behav Med 34 (3): 275-86, 2007 Nov-Dec. [PUBMED Abstract]
  17. Rimer BK, Schildkraut JM, Lerman C, et al.: Participation in a women's breast cancer risk counseling trial. Who participates? Who declines? High Risk Breast Cancer Consortium. Cancer 77 (11): 2348-55, 1996. [PUBMED Abstract]
  18. Evans DG, Burnell LD, Hopwood P, et al.: Perception of risk in women with a family history of breast cancer. Br J Cancer 67 (3): 612-4, 1993. [PUBMED Abstract]
  19. Kash KM, Holland JC, Halper MS, et al.: Psychological distress and surveillance behaviors of women with a family history of breast cancer. J Natl Cancer Inst 84 (1): 24-30, 1992. [PUBMED Abstract]
  20. Davis S, Stewart S, Bloom J: Increasing the accuracy of perceived breast cancer risk: results from a randomized trial with Cancer Information Service callers. Prev Med 39 (1): 64-73, 2004. [PUBMED Abstract]
  21. Emmons KM, Kalkbrenner KJ, Klar N, et al.: Behavioral risk factors among women presenting for genetic testing. Cancer Epidemiol Biomarkers Prev 9 (1): 89-94, 2000. [PUBMED Abstract]
  22. Kelly KM, Shedlosky-Shoemaker R, Porter K, et al.: Cancer family history reporting: impact of method and psychosocial factors. J Genet Couns 16 (3): 373-82, 2007. [PUBMED Abstract]
  23. Emery JD, Reid G, Prevost AT, et al.: Development and validation of a family history screening questionnaire in Australian primary care. Ann Fam Med 12 (3): 241-9, 2014 May-Jun. [PUBMED Abstract]
  24. Armel SR, McCuaig J, Finch A, et al.: The effectiveness of family history questionnaires in cancer genetic counseling. J Genet Couns 18 (4): 366-78, 2009. [PUBMED Abstract]
  25. Appleby-Tagoe JH, Foulkes WD, Palma L: Reading between the lines: a comparison of responders and non-responders to a family history questionnaire and implications for cancer genetic counselling. J Genet Couns 21 (2): 273-91, 2012. [PUBMED Abstract]
  26. Vogel TJ, Stoops K, Bennett RL, et al.: A self-administered family history questionnaire improves identification of women who warrant referral to genetic counseling for hereditary cancer risk. Gynecol Oncol 125 (3): 693-8, 2012. [PUBMED Abstract]
  27. Eichmeyer JN, Burnham C, Sproat P, et al.: The value of a genetic counselor: improving identification of cancer genetic counseling patients with chart review. J Genet Couns 23 (3): 323-9, 2014. [PUBMED Abstract]
  28. Tehranifar P, Wu HC, Shriver T, et al.: Validation of family cancer history data in high-risk families: the influence of cancer site, ethnicity, kinship degree, and multiple family reporters. Am J Epidemiol 181 (3): 204-12, 2015. [PUBMED Abstract]
  29. Bennett RL, Steinhaus KA, Uhrich SB, et al.: Recommendations for standardized human pedigree nomenclature. Pedigree Standardization Task Force of the National Society of Genetic Counselors. Am J Hum Genet 56 (3): 745-52, 1995. [PUBMED Abstract]
  30. Bennett RL, French KS, Resta RG, et al.: Standardized human pedigree nomenclature: update and assessment of the recommendations of the National Society of Genetic Counselors. J Genet Couns 17 (5): 424-33, 2008. [PUBMED Abstract]
  31. Wang C, Gallo RE, Fleisher L, et al.: Literacy assessment of family health history tools for public health prevention. Public Health Genomics 14 (4-5): 222-37, 2011. [PUBMED Abstract]
  32. Lu KH, Wood ME, Daniels M, et al.: American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. J Clin Oncol 32 (8): 833-40, 2014. [PUBMED Abstract]
  33. Schneider K: Collection and interpretation of cancer histories. In: Schneider KA: Counseling About Cancer: Strategies for Genetic Counseling. 2nd ed. New York, NY: Wiley-Liss, 2002, pp 129-166.
  34. Wideroff L, Garceau AO, Greene MH, et al.: Coherence and completeness of population-based family cancer reports. Cancer Epidemiol Biomarkers Prev 19 (3): 799-810, 2010. [PUBMED Abstract]
  35. Mitchell RJ, Brewster D, Campbell H, et al.: Accuracy of reporting of family history of colorectal cancer. Gut 53 (2): 291-5, 2004. [PUBMED Abstract]
  36. Schneider KA, DiGianni LM, Patenaude AF, et al.: Accuracy of cancer family histories: comparison of two breast cancer syndromes. Genet Test 8 (3): 222-8, 2004. [PUBMED Abstract]
  37. Douglas FS, O'Dair LC, Robinson M, et al.: The accuracy of diagnoses as reported in families with cancer: a retrospective study. J Med Genet 36 (4): 309-12, 1999. [PUBMED Abstract]
  38. Sijmons RH, Boonstra AE, Reefhuis J, et al.: Accuracy of family history of cancer: clinical genetic implications. Eur J Hum Genet 8 (3): 181-6, 2000. [PUBMED Abstract]
  39. Mai PL, Garceau AO, Graubard BI, et al.: Confirmation of family cancer history reported in a population-based survey. J Natl Cancer Inst 103 (10): 788-97, 2011. [PUBMED Abstract]
  40. Ozanne EM, O'Connell A, Bouzan C, et al.: Bias in the reporting of family history: implications for clinical care. J Genet Couns 21 (4): 547-56, 2012. [PUBMED Abstract]
  41. Brennan P, Claber O, Brennan T: Cancer family history triage: a key step in the decision to offer screening and genetic testing. Fam Cancer 12 (3): 497-502, 2013. [PUBMED Abstract]
  42. Beadles CA, Ryanne Wu R, Himmel T, et al.: Providing patient education: impact on quantity and quality of family health history collection. Fam Cancer 13 (2): 325-32, 2014. [PUBMED Abstract]
  43. Evans DG, Kerr B, Cade D, et al.: Fictitious breast cancer family history. Lancet 348 (9033): 1034, 1996. [PUBMED Abstract]
  44. Qureshi N, Wilson B, Santaguida P, et al.: Collection and Use of Cancer Family History in Primary Care. Evidence Report/Technology Assessment No. 159. Rockville,Md: Agency for Healthcare Research and Quality, 2007. AHRQ Pub No. 08-E001.
  45. Murff HJ, Spigel DR, Syngal S: Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA 292 (12): 1480-9, 2004. [PUBMED Abstract]
  46. Roth FL, Camey SA, Caleffi M, et al.: Consistency of self-reported first-degree family history of cancer in a population-based study. Fam Cancer 8 (3): 195-202, 2009. [PUBMED Abstract]
  47. Katki HA: Incorporating medical interventions into carrier probability estimation for genetic counseling. BMC Med Genet 8: 13, 2007. [PUBMED Abstract]
  48. Ziogas A, Horick NK, Kinney AY, et al.: Clinically relevant changes in family history of cancer over time. JAMA 306 (2): 172-8, 2011. [PUBMED Abstract]
  49. Hampel H, Bennett RL, Buchanan A, et al.: A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med 17 (1): 70-87, 2015. [PUBMED Abstract]
  50. Lindor NM, McMaster ML, Lindor CJ, et al.: Concise handbook of familial cancer susceptibility syndromes - second edition. J Natl Cancer Inst Monogr (38): 1-93, 2008. [PUBMED Abstract]
  51. Hodgson SV, Maher ER: A Practical Guide to Human Cancer Genetics. Cambridge, UK: Cambridge University Press, 1993.
  52. Mulvihill JJ: Catalog of Human Cancer Genes: McKusick's Mendelian Inheritance in Man for Clinical and Research Oncologists. Baltimore, Md: Johns Hopkins University Press, 1999.
  53. Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: John Wiley and Sons, 1998.
  54. Lewin B: Genes VII. Oxford, NY: Oxford University Press, 2000.
  55. Gelehrter TD, Collins FS, Ginsburg D: Principles of Medical Genetics. 2nd ed. Baltimore, Md: Williams and Wilkins, 1998.
  56. MacDonald DJ, Lessick M: Hereditary cancers in children and ethical and psychosocial implications. J Pediatr Nurs 15 (4): 217-25, 2000. [PUBMED Abstract]
  57. Harper PS: Practical Genetic Counselling. 3rd ed. London: Wright, 1988.
  58. Stratton MR: Exploring the genomes of cancer cells: progress and promise. Science 331 (6024): 1553-8, 2011. [PUBMED Abstract]
  59. Campeau PM, Foulkes WD, Tischkowitz MD: Hereditary breast cancer: new genetic developments, new therapeutic avenues. Hum Genet 124 (1): 31-42, 2008. [PUBMED Abstract]
  60. Freedman AN, Seminara D, Gail MH, et al.: Cancer risk prediction models: a workshop on development, evaluation, and application. J Natl Cancer Inst 97 (10): 715-23, 2005. [PUBMED Abstract]
  61. Lindor NM, Lindor RA, Apicella C, et al.: Predicting BRCA1 and BRCA2 gene mutation carriers: comparison of LAMBDA, BRCAPRO, Myriad II, and modified Couch models. Fam Cancer 6 (4): 473-82, 2007. [PUBMED Abstract]
  62. Domchek SM, Eisen A, Calzone K, et al.: Application of breast cancer risk prediction models in clinical practice. J Clin Oncol 21 (4): 593-601, 2003. [PUBMED Abstract]
  63. Weitzel JN, Lagos VI, Cullinane CA, et al.: Limited family structure and BRCA gene mutation status in single cases of breast cancer. JAMA 297 (23): 2587-95, 2007. [PUBMED Abstract]
  64. Kauff ND, Offit K: Modeling genetic risk of breast cancer. JAMA 297 (23): 2637-9, 2007. [PUBMED Abstract]
  65. Offit K, Brown K: Quantitating familial cancer risk: a resource for clinical oncologists. J Clin Oncol 12 (8): 1724-36, 1994. [PUBMED Abstract]
  66. Apicella C, Andrews L, Hodgson SV, et al.: Log odds of carrying an Ancestral Mutation in BRCA1 or BRCA2 for a Defined personal and family history in an Ashkenazi Jewish woman (LAMBDA). Breast Cancer Res 5 (6): R206-16, 2003. [PUBMED Abstract]
  67. Chenevix-Trench G, Milne RL, Antoniou AC, et al.: An international initiative to identify genetic modifiers of cancer risk in BRCA1 and BRCA2 mutation carriers: the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA). Breast Cancer Res 9 (2): 104, 2007. [PUBMED Abstract]
  68. Hoskins KF, Stopfer JE, Calzone KA, et al.: Assessment and counseling for women with a family history of breast cancer. A guide for clinicians. JAMA 273 (7): 577-85, 1995. [PUBMED Abstract]
  69. Adams-Campbell LL, Makambi KH, Palmer JR, et al.: Diagnostic accuracy of the Gail model in the Black Women's Health Study. Breast J 13 (4): 332-6, 2007 Jul-Aug. [PUBMED Abstract]
  70. Fisher ER, Land SR, Fisher B, et al.: Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: twelve-year observations concerning lobular carcinoma in situ. Cancer 100 (2): 238-44, 2004. [PUBMED Abstract]
  71. Chuba PJ, Hamre MR, Yap J, et al.: Bilateral risk for subsequent breast cancer after lobular carcinoma-in-situ: analysis of surveillance, epidemiology, and end results data. J Clin Oncol 23 (24): 5534-41, 2005. [PUBMED Abstract]
  72. Emery J, Morris H, Goodchild R, et al.: The GRAIDS Trial: a cluster randomised controlled trial of computer decision support for the management of familial cancer risk in primary care. Br J Cancer 97 (4): 486-93, 2007. [PUBMED Abstract]

Education and Counseling About Risk/Risk Communication

Specific clinical programs for risk management may be offered to persons with an increased genetic risk of cancer. These programs may differ from those offered to persons of average risk in several ways: screening may be initiated at an earlier age or involve shorter screening intervals; screening strategies not in routine use, such as screening for ovarian cancer, may be offered; and interventions to reduce cancer risk, such as risk-reducing surgery, may be offered. Current recommendations are summarized in the PDQ summaries addressing the genetics of specific cancers.

The goal of genetic education and counseling is to help individuals understand their personal risk status, their options for cancer risk management, and to explore feelings regarding their personal risk status. Counseling focuses on obtaining and giving information, promoting autonomous decision making, and facilitating informed consent if genetic testing is pursued.

Optimally, education and counseling about cancer risk includes providing the following information:

  • Purpose, strengths, and limitations of cancer risk assessment.
  • Basic genetics and patterns of inheritance.
  • Genetic basis of cancer.
  • Clinical features of relevant hereditary cancer syndromes.
  • Evidence of a hereditary cancer syndrome from the consultand's personal and family history.
  • Options for clarifying cancer risk, including genetic testing, if indicated.
  • Options available for risk management, including data (or lack of data) on the efficacy of different measures for early detection and risk reduction.
  • Signs and symptoms of cancer.

When a clinically valid genetic test is available, education and counseling for genetic testing typically includes the following:

  • Risk of having a pathogenic variant and patterns of transmission.
  • Alternatives to genetic testing.
  • Risks, benefits and limitations of genetic testing, including psychological and discriminatory risks.
  • Possible test outcomes, including likelihood of uninformative results and identifying variants of uncertain significance.
  • Sensitivity of the genetic test, including the techniques utilized to perform the test and their associated limitations.
  • Health care management options based on possible test results.
  • Implications for children and other family members based on pattern of transmission.
  • Dissemination of risk and genetic information to family members.
  • Cost associated with testing, counseling, medical management, and options for insurance coverage.
  • How genetic information and genetic test results will be recorded in the medical record.
  • Specimen storage and reuse, if applicable.

If a second session is held to disclose and interpret genetic test results, education and counseling focuses on the following:

  • Interpretation of test results.
  • Discussion of further testing that may clarify risk (e.g., large rearrangement testing and testing the other genes based on the patient's differential cancer syndrome list).
  • Assessment of the emotional and behavioral responses to genetic test results.
  • Recommendations for coping and communication strategies to address issues related to cancer risk.
  • Cancer risk management recommendations.
  • Risk analysis and dissemination of risk results to family members.

The process of counseling may require more than one visit to address medical, genetic testing, and psychosocial support issues. Additional case-related preparation time is spent before and after the consultation sessions to obtain and review medical records, complete case documentation, seek information about differential diagnoses, identify appropriate laboratories for genetic tests, find patient support groups, research resources, and communicate with or refer to other specialists.[1]

Information about inherited risk of cancer is growing rapidly. Many of the issues discussed in a counseling session may need to be revisited as new information emerges. At the end of the counseling process, individuals are typically reminded of the possibility that future research may provide new options and/or new information on risk. Individuals may be advised to check in with the health care provider periodically to determine whether new information is sufficient to merit an additional counseling session. The obligation of health care providers to recontact individuals when new genetic testing or treatment options are available is controversial, and standards have not been established.

Methods of Risk Presentation

The usage of numerical probabilities to communicate risk may overestimate the level of risk certainty, especially when wide confidence intervals exist to the estimates or when the individual may differ in important ways from the sample on which the risk estimate was derived. Also, numbers are often inadequate for expressing gut-level or emotional aspects of risk. Finally, there are wide variations in individuals’ level of understanding of mathematical concepts (i.e., numeracy). For all the above reasons, conveying risk in multiple ways, both numerically and verbally, with discussion of important caveats, may be a useful strategy to increase risk comprehension. The numerical format that facilitates the best understanding is natural frequencies because frequencies include information concerning the denominator, the reference group to which the individual may refer. In general, logarithmic scales are to be avoided.[2] Additionally, important “contextual” risks may be included with the frequency in order to increase risk comprehension; these may include how the person’s risk compares with those who do not have the risk factor in question and the risks associated with common hazards, such as being in a car accident. Additional suggestions include being consistent in risk formats (do not mix odds and percentages), using the same denominator across risk estimates, avoiding decimal points, including base rate information, and providing more explanation if the risk is less than 1%.

The communication of risk may be numerical, verbal, or visual. Use of multiple strategies may increase comprehension and retention of cancer genetic risk information.[2] Recently, use of visual risk communication strategies has increased (e.g., histograms, pie charts, and Venn diagrams). Visual depictions of risk may be very useful in avoiding problems with comprehension of numbers, but research that confirms this is lacking.[3,4] A study published in 2008 examined the use of two different visual aids to communicate breast cancer risk. Women at an increased risk of breast cancer were randomized to receive feedback via a bar graph alone or a bar graph plus a frequency diagram (i.e., highlighted human figures). Results indicate that overall, there were no differences in improved accuracy of risk perception between the two groups, but among those women who inaccurately perceived very high risk at baseline, the group receiving both visual aids showed greater improvement in accuracy.[5]

Risk Communication

The purpose of risk counseling is to provide individuals with accurate information about their risk, help them understand and interpret their risk, assist them as they use this information to make important health care decisions, and help them make the best possible adjustment to their situation. A systematic review of 28 studies that evaluated communication interventions showed that risk communication benefits users cognitively by increasing their knowledge and understanding of risk perception and does not negatively influence affect (anxiety, cancer-related worry, and depression). Risk communication does not appear to result in a change in use of screening practices and tests. Users received the most benefit from an approach utilizing risk communication along with genetic counseling.[6,7] Perceptions of risk are affected by the manner in which risk information is presented, difficulty understanding probability and heredity,[8,9] and other psychological processes on the part of individuals and providers.[10] Risk may be communicated in many ways (e.g., with numbers, words, or graphics; alone or in relation to other risks; as the probability of having an adverse event; in relative or absolute terms; and through combinations of these methods). The way in which risk information is communicated may affect the individual’s perception of the magnitude of that risk. In general, relative risk estimates (e.g., "You have a threefold increased risk of colorectal cancer") are perceived as less informative than absolute risk (e.g., "You have a 25% risk of colorectal cancer") [11] or risk information presented as a ratio (e.g., 1 in 4).[9] A strong preference for having BRCA1/2 pathogenic variant risk estimates expressed numerically is reported by women considering testing.[12] Individuals associate widely differing quantitative risks with qualitative descriptors of risk such as “rare” or “common.”[13] More research is needed on the best methods of communicating risk in order to help individuals develop an accurate understanding of their cancer risks.

Communication Strategies

Recent descriptive examination of the process of cancer genetic counseling has found that counseling sessions are predominantly focused on the biomedical teaching required to inform clients of their choices and to put genetic findings in perspective but that attention to psychosocial issues does not detract from teaching goals and may enhance satisfaction in clients undergoing counseling. For instance, one study of communication patterns in 167 pretest counseling sessions for BRCA1 found the sessions to have a predominantly biomedical and educational focus;[14] however, this approach was client focused, with the counselor and client contributing equally to the dialogue. These authors note that there was a marked diversity in counselor styles, both between counselors and within different sessions, for each counselor. The finding of a didactic style was corroborated by other researchers who examined observer-rated content checklists and videotape of 51 counseling sessions for breast cancer susceptibility.[15] Of note, genetic counselors seemed to rely on demographic information and breast cancer history to tailor genetic counseling sessions rather than client’s self-reported expectations or psychosocial factors.[16] Concurrent provision of psychosocial and scientific information may be important in reducing worry in the context of counseling about cancer genetics topics.[17] An increasing appreciation of language choices may contribute to enhanced understanding and reduced anxiety levels in the session; for example, it was noted that patients may appreciate synonymic choices for the word “mutation,” such as “altered gene”.[18] Some authors have published recommendations for cultural tailoring of educational materials for the African-American population, such as a large flip chart, including the use of simple language and pictures, culturally identifiable images (e.g., spiritual symbols and tribal patterns), bright colors, and humor.[19]

Studies have examined novel channels to communicate genetic cancer risk information, deliver psychosocial support, and standardize the genetic counseling process for individuals at increased risk of cancer.[20-27] Much of this literature has attempted to make the genetic counseling session more efficient or to limit the need for the counselor to address basic genetic principles in the session to free up time for the client’s personal and emotional concerns about his or her risk. For example, the receipt of genetic feedback for BRCA1/2 and mismatch repair gene testing by letter, rather than a face-to-face genetic counseling feedback session, has been investigated.[28] Other modalities include the development of patient assessments or checklists, CD-ROM programs, and interactive computer programs.

Patient assessments or checklists have been developed to facilitate coverage of important areas in the counseling session. One study assessed patients’ psychosocial needs before a hereditary cancer counseling session to determine the assessment’s effect on the session.[29] A total of 246 participants from two familial cancer clinics were randomly assigned to either an intervention arm in which the counselor received assessment results or a usual care control arm. Study results demonstrated that psychosocial concerns were discussed more frequently among intervention participants than among controls, without affecting session length. Moreover, cancer worry and psychological distress were significantly lower for intervention versus control participants 4 weeks after the counseling session.

A second study compared a feedback checklist completed by 197 women attending a high-risk breast clinic prior to the counseling session to convey prior genetic knowledge and misconceptions to aid the counselor in tailoring the session for that client.[22] The use of the feedback checklist led to gains in knowledge from the counseling session but did not reduce genetic counseling time, perhaps because the genetic counselor chose to spend time discussing topics such as psychosocial issues. Use of the checklist did decrease the time spent with the medical oncologist, however. The feedback checklist was compared to a CD-ROM that outlined basic genetic concepts and the benefits and limitations of testing and found that those viewing the CD-ROM spent less time with counselors and were less likely to choose to undergo genetic testing. The CD-ROM did not lead to increased knowledge of genetic concepts, as did use of the checklist.

A prospective study evaluated the effects of a CD-ROM decisional support aid for microsatellite instability (MSI) tumor testing in 239 colorectal cancer patients who met the revised Bethesda criteria but who did not meet the Amsterdam criteria.[30] The study also tested a theoretical model of factors influencing decisional conflict surrounding decisions to pursue MSI tumor testing. Within the study, half of the sample was randomly assigned to receive a brief description of MSI testing within the clinical encounter, and the other half was provided the CD-ROM decisional support aid in addition to the brief description. The CD-ROM and brief description intervention increased knowledge about MSI testing more than the brief description alone did. As a result, decisional conflict decreased because participants felt more prepared to make a decision about the test and had increased perceived benefits of MSI testing.

Other innovative strategies include educational materials and interactive computer technology. In one study, a 13-page color communication aid using a diverse format for conveying risk, including graphic representations and verbal descriptions, was developed.[23] The authors evaluated the influence of the communication aid in 27 women at high risk of a BRCA1/2 pathogenic variant and compared those who had read the aid to a comparison sample of 107 women who received standard genetic counseling. Improvements in genetic knowledge and accuracy of risk perception were documented in those who had read the aid, with no differences in anxiety or depression between groups. Personalized, interactive electronic materials have also been developed to aid in genetic education and counseling.[24,25] In one study, an interactive computer education program available prior to the genetic counseling session was compared with genetic counseling alone in women undergoing counseling for BRCA1/2 testing.[25] Use of the computer program prior to genetic counseling reduced face-time with the genetic counselor, particularly for those at lower risk of a BRCA1/2 pathogenic variant. Many of the counselors reported that their client’s use of the computer program allowed them to be more efficient and to reallocate time spent in the sessions to clients’ unique concerns.

Videoconferencing is an innovative strategy to facilitate genetic counseling sessions with clients who cannot travel to specialized clinic settings. In 37 individuals in the United Kingdom, real-time video conferencing was compared with face-to-face counseling sessions; both methods were found to improve knowledge and reduce anxiety levels.[26] Similarly, teleconferencing sessions, in which the client and genetic specialists were able to talk with each other in real time, were used in rural Maine communities [27] in the pediatric context to convey genetic information and findings for developmental delays and were found to be comparable to in-person consultations in terms of decision-making confidence and satisfaction with the consultations. An Australian study compared the experiences of 106 women who received hereditary breast and ovarian cancer genetic counseling via videoconferencing with the experiences of 89 women who received counseling face to face. Pre- and 1-month postcounseling assessments revealed no significant differences in knowledge gains, satisfaction, cancer-specific anxiety, generalized anxiety, depression, and perceived empathy of the genetic counselor.[31]

References
  1. Baker DL, Schuette JL, Uhlmann WR, eds.: A Guide to Genetic Counseling. New York, NY: Wiley-Liss, 1998.
  2. Lipkus IM: Numeric, verbal, and visual formats of conveying health risks: suggested best practices and future recommendations. Med Decis Making 27 (5): 696-713, 2007 Sep-Oct. [PUBMED Abstract]
  3. Ancker JS, Senathirajah Y, Kukafka R, et al.: Design features of graphs in health risk communication: a systematic review. J Am Med Inform Assoc 13 (6): 608-18, 2006 Nov-Dec. [PUBMED Abstract]
  4. Schapira MM, Nattinger AB, McHorney CA: Frequency or probability? A qualitative study of risk communication formats used in health care. Med Decis Making 21 (6): 459-67, 2001 Nov-Dec. [PUBMED Abstract]
  5. Ghosh K, Crawford BJ, Pruthi S, et al.: Frequency format diagram and probability chart for breast cancer risk communication: a prospective, randomized trial. BMC Womens Health 8: 18, 2008. [PUBMED Abstract]
  6. Edwards A, Gray J, Clarke A, et al.: Interventions to improve risk communication in clinical genetics: systematic review. Patient Educ Couns 71 (1): 4-25, 2008. [PUBMED Abstract]
  7. Edwards A, Unigwe S, Elwyn G, et al.: Personalised risk communication for informed decision making about entering screening programs. Cochrane Database Syst Rev (1): CD001865, 2003. [PUBMED Abstract]
  8. Marteau TM, van Duijn M, Ellis I: Effects of genetic screening on perceptions of health: a pilot study. J Med Genet 29 (1): 24-6, 1992. [PUBMED Abstract]
  9. Hopwood P, Howell A, Lalloo F, et al.: Do women understand the odds? Risk perceptions and recall of risk information in women with a family history of breast cancer. Community Genet 6 (4): 214-23, 2003. [PUBMED Abstract]
  10. Redelmeier DA, Koehler DJ, Liberman V, et al.: Probability judgement in medicine: discounting unspecified possibilities. Med Decis Making 15 (3): 227-30, 1995 Jul-Sep. [PUBMED Abstract]
  11. Malenka DJ, Baron JA, Johansen S, et al.: The framing effect of relative and absolute risk. J Gen Intern Med 8 (10): 543-8, 1993. [PUBMED Abstract]
  12. Winer E, Winer N, Bluman L, et al.: Attitudes and risk perceptions of women with breast cancer considering testing for BRCA1/2. [Abstract] Proceedings of the American Society of Clinical Oncology 16: A1937, 537a, 1997.
  13. Mazur DJ, Hickam DH: Patients' interpretations of probability terms. J Gen Intern Med 6 (3): 237-40, 1991 May-Jun. [PUBMED Abstract]
  14. Ellington L, Baty BJ, McDonald J, et al.: Exploring genetic counseling communication patterns: the role of teaching and counseling approaches. J Genet Couns 15 (3): 179-89, 2006. [PUBMED Abstract]
  15. Pieterse AH, van Dulmen S, van Dijk S, et al.: Risk communication in completed series of breast cancer genetic counseling visits. Genet Med 8 (11): 688-96, 2006. [PUBMED Abstract]
  16. Lobb EA, Butow PN, Meiser B, et al.: Tailoring communication in consultations with women from high risk breast cancer families. Br J Cancer 87 (5): 502-8, 2002. [PUBMED Abstract]
  17. Appleton S, Watson M, Rush R, et al.: A randomised controlled trial of a psychoeducational intervention for women at increased risk of breast cancer. Br J Cancer 90 (1): 41-7, 2004. [PUBMED Abstract]
  18. Hodgson J, Hughes E, Lambert C: "SLANG"--Sensitive Language and the New Genetics--an exploratory study. J Genet Couns 14 (6): 415-21, 2005. [PUBMED Abstract]
  19. Baty BJ, Kinney AY, Ellis SM: Developing culturally sensitive cancer genetics communication aids for African Americans. Am J Med Genet 118A (2): 146-55, 2003. [PUBMED Abstract]
  20. Green MJ, Peterson SK, Baker MW, et al.: Effect of a computer-based decision aid on knowledge, perceptions, and intentions about genetic testing for breast cancer susceptibility: a randomized controlled trial. JAMA 292 (4): 442-52, 2004. [PUBMED Abstract]
  21. Fransen M, Meertens R, Schrander-Stumpel C: Communication and risk presentation in genetic counseling. Development of a checklist. Patient Educ Couns 61 (1): 126-33, 2006. [PUBMED Abstract]
  22. Wang C, Gonzalez R, Milliron KJ, et al.: Genetic counseling for BRCA1/2: a randomized controlled trial of two strategies to facilitate the education and counseling process. Am J Med Genet A 134 (1): 66-73, 2005. [PUBMED Abstract]
  23. Lobb EA, Butow PN, Moore A, et al.: Development of a communication aid to facilitate risk communication in consultations with unaffected women from high risk breast cancer families: a pilot study. J Genet Couns 15 (5): 393-405, 2006. [PUBMED Abstract]
  24. Mackay J, Schulz P, Rubinelli S, et al.: Online patient education and risk assessment: project OPERA from Cancerbackup. Putting inherited breast cancer risk information into context using argumentation theory. Patient Educ Couns 67 (3): 261-6, 2007. [PUBMED Abstract]
  25. Green MJ, Peterson SK, Baker MW, et al.: Use of an educational computer program before genetic counseling for breast cancer susceptibility: effects on duration and content of counseling sessions. Genet Med 7 (4): 221-9, 2005. [PUBMED Abstract]
  26. Coelho JJ, Arnold A, Nayler J, et al.: An assessment of the efficacy of cancer genetic counselling using real-time videoconferencing technology (telemedicine) compared to face-to-face consultations. Eur J Cancer 41 (15): 2257-61, 2005. [PUBMED Abstract]
  27. Lea DH, Johnson JL, Ellingwood S, et al.: Telegenetics in Maine: Successful clinical and educational service delivery model developed from a 3-year pilot project. Genet Med 7 (1): 21-7, 2005. [PUBMED Abstract]
  28. Voorwinden JS, Jaspers JP, ter Beest JG, et al.: The introduction of a choice to learn pre-symptomatic DNA test results for BRCA or Lynch syndrome either face-to-face or by letter. Clin Genet 81 (5): 421-9, 2012. [PUBMED Abstract]
  29. Eijzenga W, Aaronson NK, Hahn DE, et al.: Effect of routine assessment of specific psychosocial problems on personalized communication, counselors’ awareness, and distress levels in cancer genetic counseling practice: a randomized controlled trial. J Clin Oncol 32 (27): 2998-3004, 2014. [PUBMED Abstract]
  30. Hall MJ, Manne SL, Winkel G, et al.: Effects of a decision support intervention on decisional conflict associated with microsatellite instability testing. Cancer Epidemiol Biomarkers Prev 20 (2): 249-54, 2011. [PUBMED Abstract]
  31. Zilliacus EM, Meiser B, Lobb EA, et al.: Are videoconferenced consultations as effective as face-to-face consultations for hereditary breast and ovarian cancer genetic counseling? Genet Med 13 (11): 933-41, 2011. [PUBMED Abstract]

The Option of Genetic Testing

Factors to Take into Consideration in Offering Testing

Indications for testing

Experts recommend offering genetic testing when a risk assessment suggests the presence of an inherited cancer syndrome for which specific genes have been identified. The American Society of Clinical Oncology (ASCO) Policy Statement on Genetic Testing for Cancer Susceptibility proposes that genetic testing be offered when the following conditions apply:[1,2]

  • An individual has a personal or family history suggestive of a genetic cancer susceptibility syndrome.
  • The results of the test can be interpreted.
  • Testing will influence medical management.

Characteristics used in making this determination are discussed in the PDQ summaries on the genetics of specific cancers. Even when individual and family history characteristics indicate a possible inherited cancer syndrome, individuals may elect not to proceed with testing after discussion of potential risks, benefits, and limitations, as discussed below. Conversely, individuals whose pedigrees are incomplete or uninformative due to very small family size, early deaths, or incomplete data on key family members may elect to pursue genetic testing in an attempt to better define their risk status. In these situations, it is particularly important that the pretest counseling fully explore the limitations of the testing process.

In 2010, ASCO updated its policy statement to address testing for low- to moderate-penetrance genes, multigene (panel) testing, and direct-to-consumer (DTC) testing. This ASCO framework (Table 1) recommends that the provider consider the evidence for clinical utility of the test in addition to whether the test was obtained through a health care provider or directly by the consumer.[1]

Table 1. Clinical Utility of Genetic/Genomic Testsa
Test Ordered By Clinical Utility Accepted Clinical Utility Uncertain
aAdapted from Robson et al.[1]
Health care Professional High-penetrance genetic variants (i.e., BRCA1, BRCA2) Low- and moderate-penetrance genetic variants (e.g., CHEK2)
Consumer High-penetrance genetic variants (i.e., BRCA1, BRCA2) Low- and moderate-penetrance genetic variants

ASCO’s position is that when a test, regardless of clinical utility, is ordered by a health care professional, the provider is responsible for organizing follow-up care based on the findings. For tests that were ordered by the consumer without health care professional involvement, management decisions are based on the evidence for clinical utility. For tests with accepted clinical utility, follow-up care can be guided by the evidence for cancer risk associated with the genetic test finding. However, in tests ordered by the consumer that have uncertain clinical utility, ASCO recommends that follow-up care consist of education regarding the lack of evidence regarding the test's clinical utility and that cancer risk management decisions be guided by established cancer risk factors.[1]

Genetic education and counseling, including the interpretation of genetic test results, will vary depending on whether a previous attempt at genetic testing has been made (see Figure 2). In general, there are two primary circumstances in which genetic testing is performed:

  • Families with evidence of an inherited susceptibility that have not had any genetic testing or in which genetic testing has not identified a pathogenic variant.
  • Families with a documented pathogenic variant.
Enlarge Flowchart showing a multi-step genetic testing algorithm for testing for cancer susceptibility.
Figure 2. This genetic testing algorithm depicts the multistep process of testing for cancer susceptibility.

Value of testing an affected family member first

Genetic susceptibility testing generally yields the most useful information when a living family member affected with the cancer of concern is tested first to determine whether a genetic basis for the cancer diagnosis can be established. If testing is deferred while follow-up with an affected relative is pending, consider providing interim cancer risk management guidelines to the unaffected proband.[3] Three possible outcomes of testing include the following (see Figure 2):

If a documented pathogenic variant (associated with cancer risk) is identified, risks are based on penetrance data for pathogenic variants of that specific gene. In addition, other family members may be tested for the presence or absence of this specific pathogenic variant. If no variant is found in an affected family member, testing is considered uninformative and thus there is no basis for testing unaffected relatives. Failure of the laboratory to detect a pathogenic variant in an affected family member does not rule out an inherited basis for the cancer in that family. Reasons why testing could be uninformative include the following:

  • The cancer in the family may be associated with a cancer susceptibility gene other than the gene that was tested.
  • The cancer in the family may be associated with a pathogenic variant, but the cancer in the specific family member who underwent testing is not associated with that variant. This can occur especially with cancers that are common in the general population, such as breast cancer or prostate cancer. The family member who is affected with the disease but is not a carrier of the pathogenic variant associated with the inherited predisposition to cancer in the family is considered a phenocopy.
  • Identifying a genetic variant may not be possible given the limited sensitivity of the laboratory techniques used to detect genetic variants. There may be additional testing available to detect certain types of variants that would have been missed by the initial genetic test.
  • The function of the gene could be altered by a pathogenic variant in a different gene.

Lastly, testing may reveal a VUS. This result means that a genetic variant has been found; however, the extent that this variant increases cancer risk, or whether it is associated with the history of cancer in the family, is uncertain. In this circumstance, some clues as to the significance of the variant can be derived from the following:

  • The location of the variant in relation to regions and function of a gene.
  • The specific change; since many variants are missense variants, not all amino acid substitutions are as significant.
  • Whether the variant has been documented in the presence of a documented pathogenic variant.
  • Whether the variant is associated with the branch in the family with the cancer and/or whether the variant tracks with the cancers in the family.

Unfortunately, even with this information, there is often insufficient evidence to document the significance of a specific variant, and further clarifying research is required.

If there is no close, living, affected relative to undergo testing, or the living affected relative declines testing, other options may be discussed with the patient and the testing laboratory. In rare instances, if proper authorization is secured from the family, testing the stored tissue of a deceased relative may be considered. However, genetic tests done on stored tissue are technically difficult and may not yield a definitive result. Therefore, testing an unaffected person without prior testing of an affected family member may be performed. In these instances, counseling includes discussing that a negative test result does not rule out the presence of a cancer susceptibility gene in the family or in the patient and may be uninformative.

Testing in families with a documented pathogenic variant

Genetic susceptibility testing for a documented pathogenic variant in the family can be very informative and will yield one of the following two results (see Figure 2):

  • Positive for the familial pathogenic variant.
  • Negative for the familial pathogenic variant.

If the familial pathogenic variant is detected in a family member, their cancer risks are based on penetrance data for pathogenic variants in that specific gene. If the documented pathogenic variant is not found in a family member, the risk of cancer in that individual is equivalent to cancer risk in the general population. However, other risk factors and family history from the side of the family not associated with the documented pathogenic variant may increase the cancer risk above the general population levels.

In summary, genetic education and counseling includes identifying the most informative person in the family to test, which may be an affected family member rather than the individual seeking genetic services. In addition, counseling includes a discussion of the limitations of the test, all possible test outcomes, and the consequences of identifying a VUS.[4]

Insurance coverage

Insurance coverage varies for cancer susceptibility testing, including multigene (panel) testing. In general, most individuals who meet specific criteria (e.g., National Comprehensive Cancer Network [NCCN] guidelines for BRCA1/2 or Lynch syndrome testing) are able to obtain insurance coverage for multigene testing.[5] Of note, some insurance companies have contracts with specific laboratories through which testing must be ordered.

The Affordable Care Act (ACA) requires that private insurers cover—with no out-of-pocket costs to the insured—genetic counseling and BRCA1/2 testing for unaffected women meeting United States Preventive Services Task Force guidelines.[6-8] Importantly, under ACA guidelines, women with a prior cancer diagnosis are not covered. The ACA does not stipulate that follow-up care based on genetic test results be covered (e.g., risk-reducing surgeries). However, some insurance companies require that pretest genetic counseling be performed by a credentialed genetics provider before testing is authorized. Before testing is ordered, it is important to verify costs and insurance coverage, including for Medicaid and Medicare patients. Medicare does not cover genetic testing if the patient has not had a cancer diagnosis associated with the pathogenic variants for which testing is ordered. In addition, unaffected individuals with Medicare are not covered for testing, even if they are tested for only a known familial pathogenic variant. Further, Medicare does not cover genetic counseling as a separately billable service.[9] For individuals without insurance coverage and the underinsured, some laboratories offer low-cost options or have financial assistance programs.

Genetic testing and assisted reproductive technology

There is a risk of carriers passing on cancer pathogenic variants to offspring. Assisted reproductive technology can be used for preimplantation genetic diagnosis (PGD) and for prenatal cancer predisposition genetic testing using chorionic villus sampling and amniocentesis.[10-12] For individuals with autosomal dominant hereditary cancer syndromes (e.g., those associated with APC, BRCA1/2, PTEN, or TP53 pathogenic variants), reproductive options exist for prenatal testing and PGD to detect offspring with one copy of the pathogenic variant (heterozygotes). However, with the advent of multigene (panel) testing, more individuals are being identified with single pathogenic variants in a broad array of genes that had been previously identified primarily in individuals with two copies of the pathogenic variant (homozygotes).

Thus, when an individual tests positive for one pathogenic variant in genes such as these, counseling about reproductive implications addresses not only the risks associated with autosomal dominant inheritance but also the potential risks of having a child with two pathogenic variants in the same gene (biallelic) that could result in a severe condition. Therefore, assessing the tested individual’s partner (i.e., his or her personal and family history and ethnicity) is important. In the unlikely event that both parents are heterozygous for specific pathogenic variants, there is a 25% risk that a child will be homozygous and could have a severe phenotype. In light of this information, couples may consider PGD or prenatal testing.

A proposed analytic framework for counseling carriers about reproduction options includes consideration of the following issues:[11]

  1. Does the cancer syndrome include childhood malignancies or significant morbidity or mortality at an early age?
  2. What is the penetrance associated with the genetic variant?
  3. How severe is the syndrome phenotype?
  4. Are there interventions available that decrease the pathogenic variant-associated cancer risk or are proven to detect cancer early when it is in a treatable form?
  5. Is there evidence of a different phenotype if an individual is a heterozygous or homozygous carrier?[13,14]

In a study of 320 patients with different hereditary cancer syndromes, most were unaware of PGD; however, the majority expressed interest in learning more about the availability of PGD.[15] Patients also preferred having a discussion about PGD with their genetic counselor or primary physician. Disease-specific factors (e.g., severity of the hereditary condition, quality of life, and medical interventions) and individual factors (e.g., gender, childbearing status, and religious beliefs) affected patient attitudes about PGD.

Determining the Test to Be Used

Genetic testing is highly specialized. A given test is usually performed in only a small number of laboratories. There are also multiple molecular testing methods available, each with its own indications, costs, strengths, and weaknesses. Depending on the method employed and the extent of the analysis, different tests for the same gene will have varying levels of sensitivity and specificity. Even assuming high analytic validity, genetic heterogeneity makes test selection challenging. A number of different genetic syndromes may underlie the development of a particular cancer type. For example, hereditary colon cancer may be due to familial adenomatous polyposis (FAP), Lynch syndrome, Peutz-Jeghers syndrome, juvenile polyposis syndrome, or other syndromes. Each of these has a different genetic basis. In addition, different genes may be responsible for the same condition (e.g., Lynch syndrome can be caused by pathogenic variants in one of several mismatch repair [MMR] genes).

In some genes, the same pathogenic variant has been found in multiple, apparently unrelated families. This observation is consistent with a founder effect, wherein a pathogenic variant identified in a contemporary population can be traced back to a small group of founders isolated by geographic, cultural, or other factors. For example, two specific BRCA1 pathogenic variants (185delAG and 5382insC) and one BRCA2 pathogenic variant (6174delT) have been reported to be common in Ashkenazi Jews. Other genes also have reported founder pathogenic variants. The presence of founder pathogenic variants has practical implications for genetic testing. Many laboratories offer directed testing specifically for ethnic-specific alleles. This greatly simplifies the technical aspects of the test but is not without limitations. For example, approximately 15% of BRCA1 and BRCA2 pathogenic variants that occur among Ashkenazim are nonfounder pathogenic variants.[16] Also, for genes in which large genome rearrangements are common in the founder population, ordering additional testing using different techniques may be needed.

Allelic heterogeneity (i.e., different variants within the same gene) can confer different risks or be associated with a different phenotype. For example, though the general rule is that adenomatous polyposis coli (APC) pathogenic variants are associated with hundreds or thousands of colonic polyps and colon cancer of the classical FAP syndrome, some APC pathogenic variants cause a milder clinical picture, with fewer polyps and lower colorectal cancer risk.[17,18] In addition, other disorders may be part of the FAP spectrum. Pathogenic variants in a certain portion of the APC gene also predispose to retinal changes, for example, when pathogenic variants in a different region of APC predispose to desmoid tumors. Thus, selection of the appropriate genetic test for a given individual requires considerable knowledge of genetic diagnostic methods, correlation between clinical and molecular findings, and access to information about rapidly changing testing options. These issues are addressed in detail in PDQ summaries on the genetics of specific cancers. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; and Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)

Multigene (panel) testing

Next-generation sequencing (NGS) has resulted in the availability of multigene testing in which many genes can be simultaneously tested for pathogenic variants, often at costs comparable to those for single-gene testing. These multigene panels can include genes with well-characterized high risks for cancer and genes that confer moderate and uncertain risks. The multigene panels can be limited to specific cancer types (e.g., breast, ovarian, colon) or can include many cancer types. This type of testing has both advantages and disadvantages, and much of the information presented in this section is not based on empirical data but rather on commentaries.

Considerations when using multigene testing

Utilizing multigene panels is complex, but there can be advantages to employing this testing approach. First, many inherited cancers result from multiple candidate genes presenting with a similar phenotype (i.e., locus heterogeneity). In this context, testing for all genes associated with a given phenotype can save both time and money.[19] Additionally, in light of the many variables that can influence family history interpretation, multigene testing may facilitate identification of the genetic basis for the cancer in the patient and/or family, especially when there may be multiple syndromes on the differential list or when the family history does not meet standard criteria for a cancer syndrome.[19,20] (Refer to the Analysis of the family history section of this summary for a list of factors that may make a family history difficult to interpret.)

There are also challenges to employing this testing approach. Multiple laboratories now offer a varying array of clinical cancer susceptibility gene panels.[21,22] Clinical multigene panels continue to evolve, thus re-testing (who and when) may be a consideration because the composition of the panels can change. Other considerations that may pose challenges to the interpretation of results include higher rates of variants of uncertain significance (VUS), especially as they differ by ethnicity, and detection of variants in genes with uncertain cancer associations.

Guidelines from the National Society of Genetic Counselors and ASCO support offering genetic testing when the following criteria are met: the personal/family history is suspicious for an inherited cancer susceptibility syndrome; the test can be interpreted; and the results will inform health care decision making.[2,23] Given that multigene tests may include genes with moderate or uncertain penetrance, all genes tested may not adhere to these professional society guidelines. (Refer to Figure 1 in the Cancer Genetics Overview PDQ summary for information about moderate and low penetrance.) Consequently, there may be limited or no evidence to support changes to medical management based on the level of risk or uncertain risk.[1,2] Furthermore, there is insufficient evidence to determine superiority of multigene testing versus phenotype-guided testing.[24] As a consequence, practice guidelines for optimal clinical use of multigene tests are only just emerging.[2,25] The NCCN and ASCO guidelines suggest that there may be efficiencies gained by using multigene testing when there is more than one cancer syndrome or gene on the differential list.[2,25] Additionally, NCCN states that there may be a role for multigene testing when a patient has a personal or family history that is consistent with an inherited susceptibility but single-gene testing has not identified a pathogenic variant.[25]

In addition to these primary criteria, providers deciding the optimal testing strategy may also consider the following: overall and patient out-of-pocket expense; insurance reimbursement; time frame to complete the test; ease of laboratory use; the probability of identifying a VUS and management of those findings, such as the reclassification process and provision of supplemental data regarding the variant; technical differences, such as the presence of a deletion /duplication assay; patient preference; and clinical history.[2,19,21,26]

Genetic education and counseling for multigene testing

ASCO has stressed the importance of genetic counseling to ensure patients are adequately informed about the implications of this type of testing and recommends that tests be ordered by cancer genetic professionals.[2,24] Yet, the use of multigene testing requires modification of traditional approaches to genetic counseling.[20,27] Optimal evidence-based counseling strategies have not yet been established. Unlike in-person, single-gene pretest genetic counseling models, these approaches have not been examined for outcomes of counseling such as comprehension, satisfaction, psychosocial outcomes, and testing uptake. Table 2 summarizes recommendations from ASCO on elements of pretest genetic counseling and informed consent for germline cancer genetic testing.[2]

Table 2. Elements of Pretest Genetic Counseling and Informed Consent for Germline Cancer Genetic Testinga
Topic Traditional Germline Cancer Genetic Testing Multigene Panel Germline Cancer Genetic Testing
aAdapted from Robson et al.[2]
Gene Information Specific gene(s) or gene variant(s) being tested. Review of specific genes included in a multigene panel may need to be batched because it is not feasible to individually cover each gene.
Risks associated with the gene(s) or gene variants(s) and implications for health care. Describe high-penetrance gene(s) and/or syndromes included in the multigene panel (i.e., hereditary breast-ovarian syndrome, Lynch syndrome, hereditary diffuse gastric cancer, Li-Fraumeni syndrome), possible detection based on personal and family history and general implications for health care.
Describe generally genes of uncertain clinical utility.
Possible Test Outcomes • Pathogenic variant detected.
• No variant detected.
• Variant of uncertain significance (VUS) detected.
  Variant in a gene for which there is:
• Limited evidence regarding penetrance.
• Discordant findings (pathogenic variant identified in a gene that is inconsistent with the patient's personal and/or family history).
Increased rate of VUS.
Risks, Benefits, and Limitations of Genetic Testing Psychosocial implications of test results.
Confidentiality considerations, including privacy, data security, and placement of results (i.e., electronic health record).
Use of DNA sample(s) for future research.
Employment and insurance discrimination risks and protections.
Costs involved in testing and scope of insurance coverage if applicable.
Whether the genetic health care professional is employed by the testing company.
Implications of Genetic Testing for Family Members Pattern of variant transmission and risks of inheritance in children and other family members.
Importance of sharing test results with family members.
Possible reproductive implications associated with pathogenic variants in genes associated with recessive conditions (i.e., ATM, Fanconi Anemia [BRCA2, PALB2], NBN, BLM).
Use of Genetic Test Results Implications of genetic test results on health care.
Outcomes of multigene testing

Results from multigene tests have several possible outcomes, including the following:[24]

  • No variant detected.
  • VUS detected.
  • Pathogenic variant in a high-penetrance gene concordant with the existing personal/family history (e.g., a germline MSH2 pathogenic variant in an individual who meets Amsterdam criteria for Lynch syndrome).
  • Pathogenic variant in a high-penetrance gene discordant with the existing personal/family history (e.g., a germline CDH1 pathogenic variant in an individual with no personal/family history of gastric cancer).
  • Pathogenic variant in a moderate-penetrance gene (e.g., CHEK2, ATM).
  • Pathogenic variant in a gene with uncertain cancer risks and/or cancer associations (e.g., POLE).

Results can also reveal more than one finding given that multiple genes are being tested simultaneously and the elevated rate of VUS.[20] There has been no assessment of outcomes of multigene tests such as comprehension, psychosocial outcomes, and uptake of cancer risk management options.

Research examining multigene testing

The range of results from NGS multigene panels is emerging in both data from clinical and laboratory series. Several of the studies are collaborations between the two. There are several important caveats about the research that has been conducted so far with regard to multigene testing:

  • The studies differ in their aims, approaches, ascertainment of subjects, and panels used.
  • Laboratory- and clinic-based studies likely differ with regard to their sampling frames (the population a study draws from and its characteristics). For example, some studies may include testing by a wide variety of health care professionals, some of whom may not be as experienced in triaging, testing, and advising high-risk patients.[28]
  • Testing methodologies also differ among laboratories regarding exon /intron coverage, read depth, Sanger sequencing confirmation, and variant interpretation.[29]
  • The genes to be tested as part of a multigene panel are constantly changing. In some studies, the composition of multigene panels changed during the course of the study, usually to include more genes.[30]
  • Some patient populations included a mix of patients already tested by traditional single-gene methods and those undergoing testing for the first time, making it difficult to establish true diagnostic yield.[31,32]

In the studies that essentially replicated previous BRCA testing, the analytic validity of the NGS multigene panel tests is equivalent to the former single-gene tests, with almost 100% concordance in patients who had both single-gene BRCA testing and multigene testing.[31,32] However, it seems clear that there are some patients in whom new pathogenic variants are found that either were or would have been missed by single-gene testing. The additional yield of multigene testing ranges according to the test used and the disease, but currently seems to be approximately 4%.[32-34] The most common non-BRCA pathogenic variants found are in CHEK2, ATM, and PALB2.[32-35] Similarly, the rates of VUS varies across studies. Table 3 presents data from a selection of the emerging reports on rates of both pathogenic variants and VUS found using the multigene tests. The table comprises studies that included more than 1,000 participants. The multigene panels are constantly changing, with genes being added or removed, therefore comparisons of the rates between studies should be made with caution. VUS rates increase with the number of genes included on the panel.[33,36] Some patients had more than one VUS, but this is not quantified. It is important to note that these data are preliminary and may change as academic clinics and commercial laboratories partner to pool the data needed to refine and standardize variant interpretation.

Table 3. Research Examining the Use of Multigene (Panel) Testing
Authors Population Clinical Description of the Population Cancer Panels Assessed Pathogenic Variant VUSa
LS = Lynch syndrome; NCCN = National Comprehensive Cancer Network; POSH = Prospective Study of Outcomes in Sporadic Versus Hereditary Breast Cancer; VUS = variant of uncertain significance.
aRefers to the percentage of patients in which at least one VUS was identified.
LaDuca et al., 2014 [30] 2,079 patients who underwent cancer panel testing between March 2012 and May 2013. Patients were ascertained from the testing laboratory's database. Tests were “clinician” ordered. Breast panel subgroup: 95.1% (831/874) had personal history of cancer or polyps Breast cancer panel (excluding BRCA1/2) (14 genes) 7.4% 19.8%
Colon panel subgroup: 95.5% (532/557) had personal history of cancer or polyps Colon cancer panel (14 genes) 9.2% 15%
Ovarian panel subgroup: 92.4% (206/223) had personal history of cancer or polyps Ovarian cancer panel (19 genes) 7.2% 25.6%
Multicancer panel subgroup: 96.7% (411/425) had personal history of cancer or polyps Multicancer panel (22 genes) 9.6% 23.5%
Couch et al., 2014 [29] 1,824 patients from 11 clinical centers participating in the Triple-Negative Breast Cancer Consortium and the POSH trial All had triple-negative breast cancer and were unselected for family history Breast cancer panel (17 genes) 14.6% (11.2% in BRCA1/2) Not reported
Tung et al., 2014 [32] 2,158 patients ascertained from commercial testing laboratory samples (cohort 1, n = 1781) and academic cancer genetic center (cohort 2, n = 377) Cohort 1: Breast cancer panel (25 genes) 13.5% 41.7% (39.3% excluding BRCA1/2)
– Personal history of breast cancer
– Test naïve
Cohort 2: Breast cancer panel (25 genes) 3.7% 41.6%
– Personal history of breast cancer
BRCA negative
Desmond et al., 2015 [34] 1,046 patients from three academic cancer genetic clinics between 2001 and 2014 All were BRCA negative. 83% (847/1,046) had personal history of breast and/or ovarian cancer Multicancer panel (25 or 29 genes) 3.8% Not reported
Yurgelun et al., 2015 [37] 1,260 patients ascertained from commercial laboratory samples in 2012–2013 All patients had a history of LS-associated cancers and/or colorectal polyps; 1,112 (88%) met NCCN guidelines for LS testing Multicancer panel (25 genes) 11% (9% in MMR pathogenic variants; 1.2% in BRCA1/2; 0.8% in APC, biallelic MUTYH, and STK11) 38%
Susswein et al., 2015 [36] 10,030 consecutive patients who underwent cancer panel testing between August 2013 and October 2014. Patients were ascertained from the clinical testing laboratory's database. Tests were "clinician" ordered. 74.8% of the population had cancer (breast, ovarian, colorectal, stomach, endometrial, pancreatic) Overall (all panels) 9% 24%
Comprehensive cancer panel (29 genes) 10% 35%
Breast/ovarian cancer panel (21 genes) 9.6% 27%
High/moderate-risk cancer panel (20 genes) 12% 30%
Colorectal cancer panel (16 genes) 11% 25%
Pancreatic cancer panel (16 genes) 6.4% 22%
Endometrial cancer panel (11 genes) 7% 12%
LS high-risk cancer panel (7 genes) 13.7% 14%
Breast high-risk cancer panel (6 genes) 3.8% 7%
Shirts et al., 2016 [38] 1,462 patients who underwent breast/ovarian (n = 1,066) or colon (n = 396) cancer panel testing from November 2011–June 2014 Patients sequentially referred for genetic testing; 80% were personally affected with cancer and 12% had more than one type of cancer Breast and ovarian cancer panel (48 genes) 12.2% (9.2% with pathogenic variant associated with clinical condition) 10.5%
Colon cancer panel (20 genes)

Regulation of genetic tests

Government regulation of genetic tests to date remains extremely limited in terms of both analytic and clinical validity with little interagency coordination.[39] The Centers for Medicare & Medicaid Services, using the Clinical Laboratory Improvement Act (CLIA), regulates all clinical human laboratory testing performed in the United States for the purposes of generating diagnostic or other health information. CLIA regulations address personnel qualifications, laboratory quality assurance standards, and documentation and validation of tests and procedures.[40] For laboratory tests themselves, CLIA categorizes tests based on the level of complexity into waived tests, moderate complexity, or high complexity. Genetic tests are considered high complexity, which indicates that a high degree of knowledge and skill is required to perform or interpret the test. Laboratories conducting high complexity tests must undergo proficiency testing at specified intervals, which consists of an external review of the laboratory's ability to accurately perform and interpret the test.[39,41] However, a specialty area specific for molecular and biologic genetic tests has yet to be established; therefore, specific proficiency testing of genetic testing laboratories is not required by CLIA.[39]

In regard to analytic validity, genetic tests fall into two primary categories; test kits and laboratory-developed tests (previously called home brews). Test kits are manufactured for use in laboratories performing the test and include all the reagents necessary to complete the analysis, instructions, performance outcomes, and details about which genetic variants can be detected. The U.S. Food and Drug Administration (FDA) regulates test kits as medical devices; however, despite more than 1,000 available genetic tests, there are fewer than ten FDA-approved test kits.[41] Laboratory-developed tests are performed in a laboratory that assembles its own testing materials in-house;[41] this category represents the most common form of genetic testing. Laboratory-developed tests are subject to the least amount of oversight, as neither CLIA nor the FDA evaluate the laboratories' proficiency in performing the test or clinical validity relative to the accuracy of the test to predict a clinical outcome.[39,41] The FDA does regulate manufactured analyte-specific reagents (ASRs) as medical devices. These small molecules are used to conduct laboratory-developed tests but can also be made by the laboratory. ASRs made in the laboratory are not subject to FDA oversight. For laboratory-developed tests utilizing manufactured commercially available ASRs, the FDA requires that the test be ordered by a health professional or other individual authorized to order the test by state law. However, this regulation does not distinguish between health providers caring for the patient or health providers who work for the laboratory offering the test.[41]

In addition to classical clinical genetic tests is the regulatory oversight of research genetic testing. Laboratories performing genetic testing on a research basis are exempt from CLIA oversight if the laboratory does not report patient-specific results for the diagnosis, prevention, or treatment of any disease or impairment or the assessment of the health of individual patients.[39] However, there are anecdotal reports of research laboratories providing test results for clinical purposes with the caveat that the laboratory recommends that testing be repeated in a clinical CLIA-approved laboratory. In addition, there is no established mechanism that determines when a test has sufficient analytic and clinical validity to be offered clinically.[41] Currently, the decision to offer a genetic test clinically is at the discretion of the laboratory director.

Evidence regarding the implications of this narrow regulatory oversight of genetic tests is limited and consists predominately of laboratory director responses to quality assurance surveys. A survey of 133 laboratory directors performing genetic tests found that 88% of laboratories employed one or more American Board of Medical Genetics (ABMG)-certified or ABMG-eligible professional geneticists, and 23% had an affiliation with at least one doctoral-prepared geneticist. Eight percent of laboratories did not employ and were not affiliated with doctoral-level genetics professionals. Laboratory-developed tests were performed in 70% of laboratories. Sixty-three percent of laboratories provided an interpretation of the test result as part of the test report.[42] Another survey of 190 laboratory directors found that 97% were CLIA-certified for high complexity testing. Sixteen percent of laboratories reported no specialty area certification; those without specialty certification represented laboratories with the most volume of tests performed and offered the most extensive test selection.[39] Of laboratories with specialty certification, not all had certification relevant to genetic tests, with 48% reporting pathology certification, 46% chemistry certification, and 41% clinical cytogenetics certification. Sixteen percent of directors reported participation in no formal external proficiency testing program, although 77% performed some informal proficiency testing when a formal external proficiency testing program was not available.

The most frequent reason cited for lack of proficiency testing participation was lack of available proficiency testing programs. Laboratory directors estimated that in the past 2 years 37% issued three or fewer incorrect reports, and 35% issued at least four incorrect reports. Analytic errors such as faulty reagent, equipment failure, or human error, increased 40% with each decrease in level of proficiency training completed.[39] An international genetic testing laboratory director survey involving 18 countries found that 64% of the 827 laboratories that responded accepted samples from outside their country.[43] Similar to the U.S. study, 74% reported participation in some form of proficiency testing. Fifty-three percent of the laboratories required a copy of the consent to perform the test, and 72% of laboratories retained specimens indefinitely that were submitted for testing.[43]

The U.S. Department of Health and Human Services Secretary’s Advisory Committee on Genetics, Health, and Society has published a detailed report regarding the adequacy and transparency of the current oversight system for genetic testing in the United States. The Committee identified gaps in the following areas:

  • Regulations governing clinical laboratory quality.
  • Oversight of the clinical validity of genetic tests.
  • The number and identification of laboratories performing genetic tests and the specific genetic tests being performed.
  • Level of current knowledge about the clinical usefulness of genetic tests.
  • Educational preparation in genetics of health providers, the public health community, patients, and consumers.

Direct-to-Consumer (DTC) Genetic Tests

Most genetic testing for cancer and other health risks is offered by health care providers on the basis of a patient’s personal history, family history, or ethnicity. Increasingly, however, individuals can order genetic testing through DTC companies without the input of health care providers. DTC tests may provide information about ancestry, paternity, propensity toward certain physical traits, risk of adverse drug reactions, and disease risks. With respect to disease risk, DTC companies have traditionally relied primarily on testing for single nucleotide polymorphisms (SNPs) to generate risk estimates for common diseases, including many cancers. However, DTC offerings are evolving to include whole-genome sequencing (WGS) and whole-exome sequencing (WES). Some DTC companies offer consumers the option of speaking with a genetics professional, but this is not required for test ordering or interpretation. This section focuses on major points related to DTC testing for cancer risks using data from SNPs, WES, or WGS.

Testing for SNPs

In the past, several DTC companies offered only SNP-based testing to generate information about health risks, including risks of cancer. Selection of SNPs may be based on data from genome-wide association studies (GWAS); however, there is no validated algorithm outlining how to generate cancer risk estimates from different SNPs, which individually are generally associated with modestly increased disease risks (usually conferring odds ratios <2.0) or modestly decreased disease risks.[44] (Refer to the GWAS section in the Cancer Genetics Overview PDQ summary for more information.) As a result, predicted disease risks from different DTC companies may yield different results. For example, a sample comparison of SNP-based risk prediction from two different companies for four different cancers yielded relative risks of 0.64 to 1.42 (excluding the three Ashkenazi BRCA1/BRCA2 founder pathogenic variants).[45] In addition, because commercial companies use different panels of SNPs, there is seldom concordance about the predicted risks for common diseases, and such risk estimates have not been prospectively validated.[46,47]

Another area of investigation is whether predicted disease risks from SNP testing are consistent with family history–based assessments. Studies using data from one commercial personal genomic testing company revealed that there was generally poor concordance between the SNP and family history risk assessment for common cancers such as breast, prostate, and colon.[48-50] Importantly, one of these studies highlighted that the majority of individuals with family histories suggestive of hereditary breast/ovarian cancer or Lynch syndrome received SNP results yielding lifetime cancer risks that were average or below average.[48]

Studies have begun to examine whether SNP testing could be used together with other established risk factors to assess the likelihood of developing cancer. For example, adding SNP data to validated breast cancer prediction tools such as those included in the National Cancer Institute's Breast Cancer Risk Assessment Tool (based on the Gail model) [51] may improve the accuracy of risk assessment.[52,53] However, this approach is not currently FDA-approved.

These findings underscore that SNP testing has not been validated as an accurate risk assessment tool and does not replace the collection, integration, and interpretation of personal and family history risk factor information by qualified health care professionals.

DTC whole-exome/genome sequencing and interpretation

Increasingly, DTC testing companies offer WGS or WES, including SNP data. (Refer to the Clinical Sequencing section in the Cancer Genetics Overview PDQ summary for a description of WGS and WES.) In addition, consumers who submit their DNA to a DTC lab for a specific indication (e.g., ancestry testing) may be given access to their raw sequence data and may consult with other companies, websites, and open-access databases for interpretation.[54,55]

Some factors to consider when determining the utility of full-sequence data for cancer (or other disease) risk assessment include the sequencing depth of the genes of interest, whether large rearrangements or gene deletions would be detected, and whether or how positive results are confirmed (e.g., through Sanger sequencing). For example, if sequencing depth is low or rare variants cannot be detected, then there is a concern about false-negative results. There is also a risk that sequence changes will be erroneously labeled as pathogenic when confirmatory testing or different interpretative approaches would determine that the variant identified is benign (false positive). When WES or WGS is performed, VUS are also likely to be identified,[56] and DTC companies have varying protocols for classification, which may or may not be consistent with national guidelines (for example, see [57]). In addition, as evidence evolves and variants are reclassified, consumers need to be aware of the process the DTC lab has, if any, for updating information and re-contacting consumers with revised interpretations.

Considerations

There may be potential benefits associated with DTC testing. DTC marketing and provision of genetic tests may promote patient autonomy.[45] Individuals may develop an increased awareness of the importance of family history, the relationship between risk and family history, the role of genetics in disease, and a better understanding of the value of genetic counseling.[58] In general, results of DTC testing may motivate individuals to seek the advice of their doctor, make lifestyle changes, and pursue screening tests.[59-61] Further, psychological distress has not been widely reported among consumers who have undergone DTC testing for a variety of conditions.[61] However, little is known about how individuals respond after learning that they carry pathogenic variants in high-risk genes such as BRCA1/BRCA2 when testing is performed within a DTC context and without traditional forms of pre- and posttest genetic education and counseling.

Given the complexity of genomic testing, several professional organizations have released position statements about DTC genetic testing. For example, in 2010, ASCO published a position statement outlining several considerations related to DTC cancer genomic tests, including those mentioned above.[1] They endorsed pre- and posttest genetic counseling and informed consent by qualified health care professionals. ASCO’s 2015 position statement on genetic and genomic testing for cancer susceptibility reinforces the importance of provider education given the complexity of genomic testing and interpretation and discusses their recommendations for regulatory review of genomic tests, including those offered by DTC companies.[2]

In 2016, a statement by the American College of Medical Genetics and Genomics about DTC genetic testing similarly endorsed the involvement of qualified genetics professionals in the processes of test ordering and interpretation.[62] The statement also emphasized the need to incorporate established methods of risk assessment into disease risk prediction (such as personal and family medical history information) and stressed that consumers need to be informed about the potential limitations and risks associated with DTC testing.

Informed Consent

Informed consent can enhance preparedness for testing, including careful weighing of benefits and limitations of testing, minimization of adverse psychosocial outcomes, appropriate use of medical options, and a strengthened provider-patient relationship based on honesty, support, and trust.

Consensus exists among experts that a process of informed consent should be an integral part of the pretest counseling process.[63] This view is driven by several ethical dilemmas that can arise in genetic susceptibility testing. The most commonly cited concern is the possibility of insurance or employment discrimination if a test result, or even the fact that an individual has sought or is seeking testing, is disclosed. In 2008, Congress passed the Genetic Information Nondiscrimination Act (GINA). This federal law provides protections related to health insurance and employment discrimination based on genetic information. However, GINA does not cover life, disability, or long-term-care insurance discrimination.[64] A related issue involves stigmatization that may occur when an individual who may never develop the condition in question, or may not do so for decades, receives genetic information and is labeled or labels himself or herself as ill. Finally, in the case of genetic testing, medical information given to one individual has immediate implications for biologic relatives. These implications include not only the medical risks but also disruptions in familial relationships. The possibility for coercion exists when one family member wants to be tested but, to do so optimally, must first obtain genetic material or information from other family members.

Inclusion of an informed consent process in counseling can facilitate patient autonomy.[65] It may also reduce the potential for misunderstanding between patient and provider. Many clinical programs provide opportunities for individuals to review their informed consent during the genetic testing and counseling process. Initial informed consent provides a verbal and/or written overview of the process.

Some programs use a second informed consent process prior to disclosure to the individual of his or her genetic test results. This process allows for the possibility that a person may change his or her mind about receiving test results. After the test result has been disclosed, a third informed consent discussion often occurs. This discussion concerns issues regarding sharing the genetic test result with health providers and/or interested family members, currently or in the future. Obtaining written permission to provide the test result to others in the family who are at risk can avoid vexing problems in the future should the individual not be available to release his or her results.

Core elements of informed consent

Major elements of an informed consent discussion are highlighted in the preceding discussion. The critical elements, as described in the literature,[1,2,66,67] include the following:

  • Elicitation and discussion of a person’s expectations, beliefs, goals, and motivations.
  • Explanation of how inheritance of genetic factors may affect cancer susceptibility.
  • Clarification of a person’s increased risk status.
  • Discussion of potential benefits, risks, and limitations of testing.
  • Discussion of costs and logistics of testing and follow-up.
  • Discussion of possible outcomes of testing (e.g., true positive, true negative, VUS, inconclusive, false positive).
  • Discussion of medical management options based on risk assessment and/or test results available for those who choose to test, for those who choose not to test, and for those who have positive, negative, or inconclusive results.
  • Data on efficacy of methods of cancer prevention and early detection.
  • Discussion of possible psychological, social, economic, and family dynamic ramifications of testing or not testing.
  • Discussion of alternatives to genetic testing (e.g., tissue banking, risk assessment without genetic testing).
  • Attainment of verbal and written informed consent or clarification of the decision to decline testing.

All individuals considering genetic testing should be informed that they have several options even after the genetic testing has been completed. They may decide to receive the results at the posttest meeting, delay result notification, or less commonly, not receive the results of testing. They should be informed that their interest in receiving results will be addressed at the beginning of the posttest meeting (see below) and that time will be available to review their concerns and thoughts on notification. It is important that individuals receive this information during the pretest counseling to ensure added comfort with the decision to decline or defer result notification even when test results become available.

Testing in children

Genetic testing for pathogenic variants in cancer susceptibility genes in children is particularly complex. While both parents [68] and providers [69] may request or recommend testing for minor children, many experts recommend that unless there is evidence that the test result will influence the medical management of the child or adolescent, genetic testing should be deferred until legal adulthood (age 18 years or older) because of concerns about autonomy, potential discrimination, and possible psychosocial effects.[70-72] A number of cancer syndromes include childhood disease risk, such as retinoblastoma, multiple endocrine neoplasia (MEN) types 1 and 2 (MEN1 and MEN2), neurofibromatosis types 1 and 2 (NF1 and NF2), Beckwith–Wiedemann syndrome, Fanconi anemia, FAP, and Von Hippel-Lindau disease (VHL).[73,74] As a consequence, decisions about genetic testing in children are made in the context of a specific gene in which a pathogenic variant is suspected. The ASCO statement on genetic testing for cancer susceptibility maintains that the decision to consider offering childhood genetic testing should take into account not only the risk of childhood malignancy but also the evidence associated with risk reduction interventions for that disorder.[1] Specifically, ASCO recommends that:

  • When screening or preventive strategies during childhood are available (e.g., MEN and FAP), testing should be encouraged on clinical grounds.
  • When no risk reduction strategies are available in childhood and the probability of developing a malignancy during childhood is very low (e.g., hereditary breast/ovarian cancer syndrome), testing should not be offered.
  • Some patients may be at risk of developing a malignancy during childhood without the availability of validated risk-reduction strategies (e.g., TP53 pathogenic variants). The decision to test in such circumstances is particularly controversial.[1]

Special considerations are required when genetic counseling and testing for pathogenic variants in cancer susceptibility genes are considered in children. The first issue is the age of the child. Young children, especially those younger than 10 years, may not be involved or may have limited involvement in the decision to be tested, and some may not participate in the genetic counseling process. In these cases, the child’s parents or other legal surrogate will be involved in the genetic counseling and will ultimately be responsible for making the decision to proceed with testing.[1,75] Counseling under these circumstances incorporates a discussion of how test results will be shared with the child when he or she is older.[1] Children aged 10 to 17 years may have more involvement in the decision-making process.[76] In a qualitative study of parents and children aged 10 to 17 years assessing decision making for genetic research participation, older, more mature children and families with open communication styles were more likely to have joint decision making. The majority of children in this study felt that they should have the right to make the final decision for genetic research participation, although many would seek input from their parents.[76] While this study is specific to genetic research participation, the findings allude to the importance children aged 10 to 17 years place on personal decision making regarding factors that impact them. Unfortunately cognitive and psychosocial development may not consistently correlate with the age of the child.[75] Therefore, careful assessment of the child’s developmental stage may help in the genetic counseling and testing process to facilitate parent and child adaptation to the test results. Another complicating factor includes potential risks for discrimination. (Refer to the Employment and Insurance Discrimination section in the Ethical, Legal, and Social Implications section of this summary for more information.)

The consequences of genetic testing in children have been reviewed.[75] In contrast to observations in adults, young children in particular are vulnerable to changes in parent and child bonding based on test results. Genetic testing could interfere with the development of self-concept and self-esteem. Children may also be at risk of developing feelings of survivor guilt or heightened anxiety. All children are especially susceptible to not understanding the testing, results, or implications for their health. As children mature, they begin to have decreased dependency on their parents while developing their personal identity. This can be altered in the setting of a serious health condition or an inherited disorder. Older children are beginning to mature physically and develop intimate relationships while also changing their idealized view of their parents. All of this can be influenced by the results of a genetic test.[75] In its recommendations for genetic testing in asymptomatic minors, the European Society of Human Genetics emphasizes that parents have a responsibility to inform their children about their genetic risk and to communicate this information in a way that is tailored to the child’s age and developmental level.[77,78]

In summary, the decision to proceed with testing in children is based on the use of the test for medical decision making for the child, the ability to interpret the test, and evidence that changes in medical decision making in childhood can positively impact health outcomes. Deferral of genetic testing is suggested when the risk of childhood malignancy is low or absent and/or there is no evidence that interventions can reduce risk.[1] When offering genetic testing in childhood, consideration of the child’s developmental stage is used to help determine his or her involvement in the testing decision and who has legal authority to provide consent. In addition, careful attention to intrafamilial issues and potential psychosocial consequences of testing in children can enable the provider to deliver support that facilitates adaptation to the test result. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers; Genetics of Colorectal Cancer; and Genetics of Endocrine and Neuroendocrine Neoplasias for more information about psychosocial research in children being tested for specific cancer susceptibility gene pathogenic variants.)

Testing in vulnerable populations

Genetic counseling and testing requires special considerations when used in vulnerable populations. In 1995, the American Society of Human Genetics published a position statement on the ethical, legal, and psychosocial implications of genetic testing in children and adolescents as a vulnerable population.[71] However, vulnerable populations encompass more than just children. Federal policy applicable to research involving human subjects, 45 CFR Code of Federal Regulations part 46 Protection Of Human Subjects, considers the following groups as potentially vulnerable populations: prisoners, traumatized and comatose patients, terminally ill patients, elderly/aged persons who are cognitively impaired and/or institutionalized, minorities, students, employees, and individuals from outside the United States. Specific to genetic testing, the International Society of Nurses in Genetics further expanded the definition of vulnerable populations to also include individuals with hearing and language deficits or conditions limiting communication (for example, language differences and concerns with reliable translation), cognitive impairment, psychiatric disturbances, clients undergoing stress due to a family situation, those without financial resources, clients with acute or chronic illness and in end-of-life, and those in whom medication may impair reasoning.

Genetic counseling and testing in vulnerable populations raises special considerations. The aim of genetic counseling is to help people understand and adapt to the medical, psychological, and familial implications of genetic contributions to disease, which in part involves the meaningful exchange of factual information.[79] In a vulnerable population, health care providers need to be sensitive to factors that can impact the ability of the individual to comprehend the information. In particular, in circumstances of cognitive impairment or intellectual disability, special attention is paid to whether the individual’s legally authorized representative should be involved in the counseling, informed consent, and testing process.

Providers need to assess all patients for their ability to make an uncoerced, autonomous, informed decision prior to proceeding with genetic testing. Populations that do not seem vulnerable (e.g., legally adult college students) may actually be deemed vulnerable because of undue coercion for testing by their parents or the threat of withholding financial support by their parents based on a testing decision inconsistent with the parent’s wishes. Alteration of the genetic counseling and testing process may be necessary depending on the situation, such as counseling and testing in terminally ill individuals who opt for testing for the benefit of their children, but given their impending death, results may have no impact on their own health care or may not be available before their death. In summary, genetic counseling and testing requires that the health care provider assess all individuals for any evidence of vulnerability, and if present, be sensitive to those issues, modify genetic counseling based on the specific circumstances, and avoid causing additional harm.

Importance of Pretest Counseling

The complexity of genetic testing for cancer susceptibility has led experts to suggest that careful, in-depth counseling should precede any decision about the use of testing, in keeping with the accepted principles for the use of genetic testing.[80]

Qualitative and quantitative research studies indicate that families hold a variety of beliefs about the inheritance of characteristics within families; some of these beliefs are congruent with current scientific understanding, whereas others are not.[81-83] These beliefs may be influenced by education, personal and family experiences, and cultural background. Because behavior is likely to be influenced by these beliefs, the usefulness of genetic information may depend on recognizing and addressing the individual’s preexisting cognitions. This process begins with initial discussion and continues throughout the genetic counseling process.

Psychological Impact of Genetic Information/Test Results on the Individual

An accurate assessment of psychosocial functioning and emotional factors related to testing motivation and potential impact and utilization is an important part of pretest counseling.[84-88] Generally, a provider inquires about a person’s emotional response to the family history of cancer and also about a person’s response to his or her own risk of developing cancer. People have various coping strategies for dealing with stressful circumstances such as genetic risk. Identifying these strategies and ascertaining how well or poorly they work will have implications for the support necessary during posttest counseling and will help personalize the discussion of anticipated risks and benefits of testing. Taking a brief history of past and current psychiatric symptoms (e.g., depression, extreme anxiety, or suicidality) will allow for an assessment of whether this individual is at particular risk of adverse effects after disclosure of results. In such cases, further psychological assessment may be indicated.

In addition, cognitive deficits in the person being counseled may significantly limit understanding of the genetic information provided and hinder the ability to give informed consent and may also require further psychological assessment. Emotional responses to cancer risk may also affect overall mood and functioning in other areas of life such as home, work, and personal health management, including cancer screening practices.[89] Education and genetic counseling sessions provide an ongoing opportunity for informal assessment of affective and cognitive aspects of the communication process. Since behavioral factors influence adherence to screening and surveillance recommendations, consideration of emotional barriers is important in helping a person choose prevention strategies and in discussing the potential utility of genetic testing.[90,91]

The discussion of issues such as history of depression, anxiety, and suicidal thoughts or tendencies requires sensitivity to the individual. The individual must be assured that the counseling process is a collaborative effort to minimize intrusiveness while maximizing benefits. Determining whether the individual is currently receiving treatment for major psychiatric illness is an important part of the counseling process. Consultation with a mental health professional familiar with psychological assessments may be useful to help the provider develop the strategies for these discussions. It also may be beneficial for the individual to be given standard psychological self-report instruments that assess levels of depression, anxiety, and other psychiatric difficulties that he or she may be experiencing. This step provides objective comparisons with already established normative data.[92,93]

In addition to the clinical assessment of psychological functioning, several instruments for cancer patients and people at increased risk of cancer have been utilized to assess psychological status. These include the Center for Epidemiological Studies-Depression scale,[94] the Profile of Mood States,[95] the Hospital Anxiety and Depression Scale,[96] and the Brief Symptom Inventory.[97] Research programs have included one or more of these instruments as a way of helping refine the selection of people at increased risk of adverse psychosocial consequences of genetic testing. Psychological assessments are an ongoing part of genetic counseling. Some individuals with symptoms of increased distress, extreme avoidance of affect, or other marked psychiatric symptoms may benefit from a discussion with, or evaluation by, a mental health professional. It may be suggested to some people (generally, a very small percentage of any population) that testing be postponed until greater emotional stability has been established.

Psychological Impact of Genetic Information/Test Results on the Family

In addition to making an assessment of the family history of cancer, the family as a social system may also be assessed as part of the process of cancer genetic counseling. Hereditary susceptibility to cancer may affect social interactions and attitudes toward the family.[98]

In assessing families, characteristics that may be relevant are the organization of the family (including recognition of individuals who propose to speak for or motivate other family members), patterns of communication within the family, cohesion or closeness of family members (or lack thereof), and the family beliefs and values that affect health behaviors. Ethnocultural factors may also play an important role in guiding behavior in some families.

Assessment also evaluates the impact of the family’s prior experience with illness on their attitudes and behaviors related to genetic counseling and testing. Prior experience with cancer diagnosis and treatment, loss due to cancer, and the family members’ interaction with the medical community may heavily influence attitudes toward receiving genetic information and may play a major role in the emotional state of individuals presenting for genetic services.

The practitioner may use the above framework to guide inquiries about the relationship of the individual to (1) the affected members of the family or (2) others who are considering or deciding against the consideration of genetic counseling or testing. Inquiries about how the family shares (or does not share) information about health, illness, and genetic susceptibility may establish whether the individual feels under pressure from other family members or anticipates difficulty in sharing genetic information obtained from counseling or testing. Inquiries about the present health (new diagnoses or deaths from cancer) or relationship status (divorce, marriage, grieving) of family members may inform the provider about the timing of the individual’s participation in counseling or testing and may also reveal possible contraindications for testing at present.

In addition to using a pedigree to evaluate family health history, tools such as the genogram and ecomap can provide specific information regarding the nature of interpersonal relationships within the family and the connections with social networks outside of the family.[99-101]

Evidence from a study of 297 persons from 38 Lynch syndrome–affected families suggested that the timing of genetic counseling and testing services may influence psychological test-related distress responses. Specifically, family members in the same generation as the index case were more likely to experience greater test-related distress with increasingly longer lengths of time between the index case's receipt of MMR pathogenic variant results and the provision of genetic counseling and testing services to family members. However, it was unclear whether time lapses were due to a delay in the index case communicating test results or the family member choosing to delay genetic testing, despite being aware of the index case’s results.[102]

More specific information about family functioning in coping with hereditary cancers can be found in the psychosocial or counseling sections of PDQ summaries on the genetics of specific types of cancer. (Refer to the PDQ summaries on Genetics of Breast and Gynecologic Cancers and Genetics of Colorectal Cancer for more information.)

Exploration of potential risks, benefits, burdens, and limitations of genetic susceptibility testing

There is substantial evidence that many people do not understand the potential limitations of genetic testing and may give too much weight to the potential benefits.[103-105] Counseling provides the opportunity to present a balanced view of the potential risks and benefits of testing and to correct misconceptions. It may be helpful to ask individuals to identify their perceptions about the pros and cons of testing as part of this discussion.

  1. Potential burdens of a test result that is uninformative or of uncertain significance.

    In the absence of a known pathogenic variant in the family, a negative test result is not informative. In this situation, the tested person’s risk status remains the same as it was prior to testing. One study of 183 women with an uninformative BRCA test result found that most women understood the implications of the test result, and it did not alter their intention to undergo a high-risk screening regimen.[106,107] If the test identifies a new variant of unknown clinical significance, the test result is of uncertain significance and cannot be used to revise the tested person’s risk estimate. Subsequent research, however, may provide information about the variant's effect (or lack of effect) on cancer risk.

    Potential burdens

    • Need to evaluate other family members to determine the significance of variants not known to be disease related.
    • Persistent uncertainty about risk status, which may result in a recommendation for intensive monitoring if a hereditary predisposition cannot be ruled out with certainty.
    • Lack of evidence-based guidance regarding prevention or surveillance strategies.
    • Continuing anxiety, frustration, and other adverse psychological sequelae associated with uncertainty because no definitive answer has been provided.
    • High monetary cost of testing.
  2. Potential benefits and burdens of a positive test in an unaffected, at-risk individual when a disease-related pathogenic variant has been previously identified in the family.

    Potential benefits

    • Elimination of uncertainty about inherited susceptibility for an individual.
    • Potential for reduction in future morbidity and mortality through enhanced cancer risk management strategies (i.e., increased screening, adoption of a healthy lifestyle, and avoidance of risk factors).
    • Opportunity to reduce cancer risk through chemoprevention and risk-reducing surgery.
    • Opportunity to inform relatives about the likelihood that they have the family pathogenic variant and about the availability of genetic testing, cancer risk assessment, and management services.

    Potential burdens

    • Neglect of screening and surveillance resulting from increased anxiety about being a carrier of a pathogenic variant.
    • Psychological distress, including anxiety, depression, reduced self-esteem.
    • Increased worry about cancer due to unproven effectiveness of current interventions to reduce risk.
    • Risks and costs of increased screening or prophylaxis.
    • Strained/altered relationships within family.
    • Guilt about possible transmission of genetic risk to children.
    • Potential insurance, employment, or social discrimination.
  3. Potential benefits and burdens of a negative test result when a disease-related pathogenic variant has been identified in the family.

    Potential benefits

    • Reassurance and reduction of anxiety about personal cancer risk due to heredity.
    • Avoidance of unnecessary intensive monitoring and prevention strategies.
    • Avoidance of aggressive interventions such as risk-reducing surgery.
    • Relief that children are not at increased risk.

    Potential burdens

    • Neglect of routine surveillance resulting from misunderstanding of a negative test result. The patient remains at the general population risk and may be at increased risk depending on his or her personal risk factors and any risk associated with the other branch of the family.
    • Adjustment to the change in expected life course.
    • Survivor guilt.
    • Strained relationship with others in family.
    • Regret over previous decisions (e.g., having had risk-reducing surgery prior to being tested).
  4. Potential benefits and burdens of a positive test result in an individual who is the first identified carrier in a family.[4]

    Potential benefits

    • No need to rely on other family members for informative test results.
    • Potential for risk reduction in future morbidity and mortality through enhanced cancer risk management strategies (i.e., increased screening and surveillance, chemoprevention, and risk-reducing surgery).
    • Opportunity to inform relatives about the likelihood that they have the family pathogenic variant and about the availability of genetic testing, cancer risk assessment, and management services.

    Potential burdens

    • Confronting ethical dilemmas about who should receive the information, what should be conveyed, and when it should be conveyed to specific family members.
    • Coping with potential personal distress in conveying the information.
    • Coping with family members' potential distress and reaction to the information.
    • Feeling unprepared for the tasks associated with disseminating genetic information through the family.
    • Loss of privacy.
    • Coping with potential personal psychological distress and reaction to the information.

Posttest education and result notification

The primary component of the posttest session is result notification. An individual may change his or her mind about receiving results, however, until the moment of results disclosure. Therefore, one typically begins the disclosure session by confirming that test results are still desired. Some people may decline or delay receipt of test results. The percentage of people who will make this decision is unknown. Such people need ongoing follow-up and the opportunity to receive test results in the future.

Once confirmed, people appreciate direct, immediate reporting of the results; they often describe the wait for results as one of the most stressful aspects of undergoing testing.[108] Often, people need a few minutes of privacy to gather their composure after hearing their test results. Sometimes this precludes all but the briefest discussion at the initial posttest visit. Usually, individuals who have been properly prepared through the pretest counseling process do not exhibit disabling distress. Although it is rare that an acute psychological reaction will occur at disclosure, it is useful for providers of genetic test results to establish a relationship with a mental health provider who can be consulted should extreme reactions occur or who can be available by referral for people seeking further exploration of emotional issues.

Either at the time of disclosure or shortly thereafter, a session for the provider and the individual to consider the genetic, medical, psychological, and social ramifications of the test result is advisable. Despite having extensive pretest education, people may still be confused about the implications and meaning of the test results. Examples of frequently documented misconceptions include the belief that a positive result means that cancer is present or certain to develop; the belief that a negative result means that cancer will never occur; and failure to understand the uncertainty inherent in certain test results, as when only a limited gene panel was examined. Regarding medical implications, it is important to inform the person of risk implications and management options for all of the cancer types associated with an inherited syndrome and to revisit options for risk management.

Posttest counseling may include consideration of the implications of the test results for other family members. It has been suggested that some individuals affected by an inherited disorder agree to have genetic testing performed in order to acquire information that could be shared with family members. There is evidence that implementation of a follow-up counseling program with the index patient, after test results are revealed, will significantly increase the proportion of relatives informed of their genetic risk. Follow-up counseling may include telephone conversations with the index patient verifying which family members have been contacted and an offer to assist with conveying information to family members.[109] Some experts have suggested that if a test result is positive, plans should be made at this time for the notification, education, and counseling of other relatives based on the test result of the individual. Written materials, brochures, or personal letters may aid people in informing the appropriate relatives about genetic risk.

When a test result is negative, the posttest session may be briefer. It is important, however, to discuss genetic, medical, and psychological implications of a negative result in a family with a known pathogenic variant. For example, it is essential that the person understand that the general population risks for relevant cancer types still apply and that the person’s individual risk of cancer may still be influenced by other risk factors and family history from the other side of the family. Furthermore, people may be surprised to feel distress even when a test is negative. This outcome has been documented in the context of BRCA1/2 pathogenic variant testing [110] and may also be anticipated in other cancer susceptibility testing. Posttest results discussion of such distress may lead to referral for additional counseling in some cases.

Many individuals benefit from follow-up counseling and consultation with medical specialists after disclosure of test results. This provides an opportunity for further discussion of feelings about their risk status, options for risk management including screening and detection procedures, and implications of the test results for other family members.

References
  1. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
  2. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
  3. Gustafson SL, Raymond VM, Marvin ML, et al.: Outcomes of genetic evaluation for hereditary cancer syndromes in unaffected individuals. Fam Cancer 14 (1): 167-74, 2015. [PUBMED Abstract]
  4. Riley BD, Culver JO, Skrzynia C, et al.: Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns 21 (2): 151-61, 2012. [PUBMED Abstract]
  5. Clain E, Trosman JR, Douglas MP, et al.: Availability and payer coverage of BRCA1/2 tests and gene panels. Nat Biotechnol 33 (9): 900-2, 2015. [PUBMED Abstract]
  6. Walcott FL, Dunn BK: Legislation in the genomic era: the Affordable Care Act and genetic testing for cancer risk assessment. Genet Med 17 (12): 962-4, 2015. [PUBMED Abstract]
  7. U.S. Department of Health & Human Services: Preventive Services Covered Under the Affordable Care Act. Washington, DC: U.S. Department of Health & Human Services, 2010. Available online. Last accessed August 15, 2016.
  8. The Center for Consumer Information & Insurance Oversight: Affordable Care Act Implementation FAQs - Set 12. Baltimore, Md: Centers for Medicare & Medicaid Services, 2013. Available online. Last accessed August 15, 2016.
  9. Facing Our Risk of Cancer Empowered (FORCE): Paying for Genetic Services. Tampa, FL: FORCE, 2016. Available online. Last accessed November 10, 2016.
  10. Offit K, Kohut K, Clagett B, et al.: Cancer genetic testing and assisted reproduction. J Clin Oncol 24 (29): 4775-82, 2006. [PUBMED Abstract]
  11. Offit K, Sagi M, Hurley K: Preimplantation genetic diagnosis for cancer syndromes: a new challenge for preventive medicine. JAMA 296 (22): 2727-30, 2006. [PUBMED Abstract]
  12. Wang CW, Hui EC: Ethical, legal and social implications of prenatal and preimplantation genetic testing for cancer susceptibility. Reprod Biomed Online 19 (Suppl 2): 23-33, 2009. [PUBMED Abstract]
  13. Meyer S, Tischkowitz M, Chandler K, et al.: Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling. J Med Genet 51 (2): 71-5, 2014. [PUBMED Abstract]
  14. Sawyer SL, Tian L, Kähkönen M, et al.: Biallelic mutations in BRCA1 cause a new Fanconi anemia subtype. Cancer Discov 5 (2): 135-42, 2015. [PUBMED Abstract]
  15. Rich TA, Liu M, Etzel CJ, et al.: Comparison of attitudes regarding preimplantation genetic diagnosis among patients with hereditary cancer syndromes. Fam Cancer 13 (2): 291-9, 2014. [PUBMED Abstract]
  16. Frank TS, Deffenbaugh AM, Reid JE, et al.: Clinical characteristics of individuals with germline mutations in BRCA1 and BRCA2: analysis of 10,000 individuals. J Clin Oncol 20 (6): 1480-90, 2002. [PUBMED Abstract]
  17. Nieuwenhuis MH, Vasen HF: Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature. Crit Rev Oncol Hematol 61 (2): 153-61, 2007. [PUBMED Abstract]
  18. Knudsen AL, Bülow S, Tomlinson I, et al.: Attenuated familial adenomatous polyposis: results from an international collaborative study. Colorectal Dis 12 (10 Online): e243-9, 2010. [PUBMED Abstract]
  19. Fecteau H, Vogel KJ, Hanson K, et al.: The evolution of cancer risk assessment in the era of next generation sequencing. J Genet Couns 23 (4): 633-9, 2014. [PUBMED Abstract]
  20. Hiraki S, Rinella ES, Schnabel F, et al.: Cancer risk assessment using genetic panel testing: considerations for clinical application. J Genet Couns 23 (4): 604-17, 2014. [PUBMED Abstract]
  21. Hall MJ, Forman AD, Pilarski R, et al.: Gene panel testing for inherited cancer risk. J Natl Compr Canc Netw 12 (9): 1339-46, 2014. [PUBMED Abstract]
  22. Easton DF, Pharoah PD, Antoniou AC, et al.: Gene-panel sequencing and the prediction of breast-cancer risk. N Engl J Med 372 (23): 2243-57, 2015. [PUBMED Abstract]
  23. Berliner JL, Fay AM, Cummings SA, et al.: NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. J Genet Couns 22 (2): 155-63, 2013. [PUBMED Abstract]
  24. Robson M: Multigene panel testing: planning the next generation of research studies in clinical cancer genetics. J Clin Oncol 32 (19): 1987-9, 2014. [PUBMED Abstract]
  25. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian. Version 2.2016. Fort Washington, PA: National Comprehensive Cancer Network, 2016. Available online with free registration. Last accessed October 6, 2016.
  26. Wolfe Schneider K, Anguiano A, Axell L, et al.: Collaboration of colorado cancer genetic counselors to integrate next generation sequencing panels into clinical practice. J Genet Couns 23 (4): 640-6, 2014. [PUBMED Abstract]
  27. Domchek SM, Bradbury A, Garber JE, et al.: Multiplex genetic testing for cancer susceptibility: out on the high wire without a net? J Clin Oncol 31 (10): 1267-70, 2013. [PUBMED Abstract]
  28. Cragun D, Radford C, Dolinsky JS, et al.: Panel-based testing for inherited colorectal cancer: a descriptive study of clinical testing performed by a US laboratory. Clin Genet 86 (6): 510-20, 2014. [PUBMED Abstract]
  29. Couch FJ, Hart SN, Sharma P, et al.: Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 33 (4): 304-11, 2015. [PUBMED Abstract]
  30. LaDuca H, Stuenkel AJ, Dolinsky JS, et al.: Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients. Genet Med 16 (11): 830-7, 2014. [PUBMED Abstract]
  31. Kurian AW, Hare EE, Mills MA, et al.: Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment. J Clin Oncol 32 (19): 2001-9, 2014. [PUBMED Abstract]
  32. Tung N, Battelli C, Allen B, et al.: Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer 121 (1): 25-33, 2015. [PUBMED Abstract]
  33. Lincoln SE, Kobayashi Y, Anderson MJ, et al.: A Systematic Comparison of Traditional and Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Genes in More Than 1000 Patients. J Mol Diagn 17 (5): 533-44, 2015. [PUBMED Abstract]
  34. Desmond A, Kurian AW, Gabree M, et al.: Clinical Actionability of Multigene Panel Testing for Hereditary Breast and Ovarian Cancer Risk Assessment. JAMA Oncol 1 (7): 943-51, 2015. [PUBMED Abstract]
  35. Kapoor NS, Curcio LD, Blakemore CA, et al.: Multigene Panel Testing Detects Equal Rates of Pathogenic BRCA1/2 Mutations and has a Higher Diagnostic Yield Compared to Limited BRCA1/2 Analysis Alone in Patients at Risk for Hereditary Breast Cancer. Ann Surg Oncol 22 (10): 3282-8, 2015. [PUBMED Abstract]
  36. Susswein LR, Marshall ML, Nusbaum R, et al.: Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med 18 (8): 823-32, 2016. [PUBMED Abstract]
  37. Yurgelun MB, Allen B, Kaldate RR, et al.: Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology 149 (3): 604-13.e20, 2015. [PUBMED Abstract]
  38. Shirts BH, Casadei S, Jacobson AL, et al.: Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med 18 (10): 974-81, 2016. [PUBMED Abstract]
  39. Hudson KL, Murphy JA, Kaufman DJ, et al.: Oversight of US genetic testing laboratories. Nat Biotechnol 24 (9): 1083-90, 2006. [PUBMED Abstract]
  40. Schwartz MK: Genetic testing and the clinical laboratory improvement amendments of 1988: present and future. Clin Chem 45 (5): 739-45, 1999. [PUBMED Abstract]
  41. Javitt GH, Hudson K: Federal neglect: regulation of genetic testing. Issues Sci Technol 22: 58-66, 2006. Also available online. Last accessed April 21, 2016.
  42. McGovern MM, Benach M, Wallenstein S, et al.: Personnel standards and quality assurance practices of biochemical genetic testing laboratories in the United States. Arch Pathol Lab Med 127 (1): 71-6, 2003. [PUBMED Abstract]
  43. McGovern MM, Elles R, Beretta I, et al.: Report of an international survey of molecular genetic testing laboratories. Community Genet 10 (3): 123-31, 2007. [PUBMED Abstract]
  44. Couch FJ, Nathanson KL, Offit K: Two decades after BRCA: setting paradigms in personalized cancer care and prevention. Science 343 (6178): 1466-70, 2014. [PUBMED Abstract]
  45. Bellcross CA, Page PZ, Meaney-Delman D: Direct-to-consumer personal genome testing and cancer risk prediction. Cancer J 18 (4): 293-302, 2012 Jul-Aug. [PUBMED Abstract]
  46. Swan M: Multigenic condition risk assessment in direct-to-consumer genomic services. Genet Med 12 (5): 279-88, 2010. [PUBMED Abstract]
  47. Kalf RR, Mihaescu R, Kundu S, et al.: Variations in predicted risks in personal genome testing for common complex diseases. Genet Med 16 (1): 85-91, 2014. [PUBMED Abstract]
  48. Aiyar L, Shuman C, Hayeems R, et al.: Risk estimates for complex disorders: comparing personal genome testing and family history. Genet Med 16 (3): 231-7, 2014. [PUBMED Abstract]
  49. Heald B, Edelman E, Eng C: Prospective comparison of family medical history with personal genome screening for risk assessment of common cancers. Eur J Hum Genet 20 (5): 547-51, 2012. [PUBMED Abstract]
  50. Bloss CS, Topol EJ, Schork NJ: Association of direct-to-consumer genome-wide disease risk estimates and self-reported disease. Genet Epidemiol 36 (1): 66-70, 2012. [PUBMED Abstract]
  51. Gail MH, Brinton LA, Byar DP, et al.: Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 81 (24): 1879-86, 1989. [PUBMED Abstract]
  52. McCarthy AM, Armstrong K, Handorf E, et al.: Incremental impact of breast cancer SNP panel on risk classification in a screening population of white and African American women. Breast Cancer Res Treat 138 (3): 889-98, 2013. [PUBMED Abstract]
  53. Mealiffe ME, Stokowski RP, Rhees BK, et al.: Assessment of clinical validity of a breast cancer risk model combining genetic and clinical information. J Natl Cancer Inst 102 (21): 1618-27, 2010. [PUBMED Abstract]
  54. Glusman G, Cariaso M, Jimenez R, et al.: Low budget analysis of Direct-To-Consumer genomic testing familial data. F1000Res 1: 3, 2012. [PUBMED Abstract]
  55. Cariaso M, Lennon G: SNPedia: a wiki supporting personal genome annotation, interpretation and analysis. Nucleic Acids Res 40 (Database issue): D1308-12, 2012. [PUBMED Abstract]
  56. Berg JS, Khoury MJ, Evans JP: Deploying whole genome sequencing in clinical practice and public health: meeting the challenge one bin at a time. Genet Med 13 (6): 499-504, 2011. [PUBMED Abstract]
  57. Richards S, Aziz N, Bale S, et al.: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17 (5): 405-24, 2015. [PUBMED Abstract]
  58. McCabe LL, McCabe ER: Direct-to-consumer genetic testing: access and marketing. Genet Med 6 (1): 58-9, 2004 Jan-Feb. [PUBMED Abstract]
  59. Bansback N, Sizto S, Guh D, et al.: The effect of direct-to-consumer genetic tests on anticipated affect and health-seeking behaviors: a pilot survey. Genet Test Mol Biomarkers 16 (10): 1165-71, 2012. [PUBMED Abstract]
  60. Kaufman DJ, Bollinger JM, Dvoskin RL, et al.: Risky business: risk perception and the use of medical services among customers of DTC personal genetic testing. J Genet Couns 21 (3): 413-22, 2012. [PUBMED Abstract]
  61. Bloss CS, Schork NJ, Topol EJ: Effect of direct-to-consumer genomewide profiling to assess disease risk. N Engl J Med 364 (6): 524-34, 2011. [PUBMED Abstract]
  62. ACMG Board of Directors: Direct-to-consumer genetic testing: a revised position statement of the American College of Medical Genetics and Genomics. Genet Med 18 (2): 207-8, 2016. [PUBMED Abstract]
  63. Geller G, Botkin JR, Green MJ, et al.: Genetic testing for susceptibility to adult-onset cancer. The process and content of informed consent. JAMA 277 (18): 1467-74, 1997. [PUBMED Abstract]
  64. Hudson KL, Holohan MK, Collins FS: Keeping pace with the times--the Genetic Information Nondiscrimination Act of 2008. N Engl J Med 358 (25): 2661-3, 2008. [PUBMED Abstract]
  65. Geller G, Doksum T, Bernhardt BA, et al.: Participation in breast cancer susceptibility testing protocols: influence of recruitment source, altruism, and family involvement on women's decisions. Cancer Epidemiol Biomarkers Prev 8 (4 Pt 2): 377-83, 1999. [PUBMED Abstract]
  66. American College of Medical Genetics: Genetic susceptibility to breast and ovarian cancer: assessment, counseling and testing guidelines. New York: New York State Department of Health, American College of Medical Genetics Foundation, 1999.
  67. McKinnon WC, Baty BJ, Bennett RL, et al.: Predisposition genetic testing for late-onset disorders in adults. A position paper of the National Society of Genetic Counselors. JAMA 278 (15): 1217-20, 1997. [PUBMED Abstract]
  68. Bradbury AR, Patrick-Miller L, Egleston B, et al.: Parent opinions regarding the genetic testing of minors for BRCA1/2. J Clin Oncol 28 (21): 3498-505, 2010. [PUBMED Abstract]
  69. O'Neill SC, Peshkin BN, Luta G, et al.: Primary care providers' willingness to recommend BRCA1/2 testing to adolescents. Fam Cancer 9 (1): 43-50, 2010. [PUBMED Abstract]
  70. Nelson RM, Botkjin JR, Kodish ED, et al.: Ethical issues with genetic testing in pediatrics. Pediatrics 107 (6): 1451-5, 2001. [PUBMED Abstract]
  71. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. American Society of Human Genetics Board of Directors, American College of Medical Genetics Board of Directors. Am J Hum Genet 57 (5): 1233-41, 1995. [PUBMED Abstract]
  72. Wertz DC, Fanos JH, Reilly PR: Genetic testing for children and adolescents. Who decides? JAMA 272 (11): 875-81, 1994. [PUBMED Abstract]
  73. Field M, Shanley S, Kirk J: Inherited cancer susceptibility syndromes in paediatric practice. J Paediatr Child Health 43 (4): 219-29, 2007. [PUBMED Abstract]
  74. Tischkowitz M, Rosser E: Inherited cancer in children: practical/ethical problems and challenges. Eur J Cancer 40 (16): 2459-70, 2004. [PUBMED Abstract]
  75. Fanos JH: Developmental tasks of childhood and adolescence: implications for genetic testing. Am J Med Genet 71 (1): 22-8, 1997. [PUBMED Abstract]
  76. Bernhardt BA, Tambor ES, Fraser G, et al.: Parents' and children's attitudes toward the enrollment of minors in genetic susceptibility research: implications for informed consent. Am J Med Genet A 116 (4): 315-23, 2003. [PUBMED Abstract]
  77. European Society of Human Genetics: Genetic testing in asymptomatic minors: Recommendations of the European Society of Human Genetics. Eur J Hum Genet 17 (6): 720-1, 2009. [PUBMED Abstract]
  78. Borry P, Evers-Kiebooms G, Cornel MC, et al.: Genetic testing in asymptomatic minors: background considerations towards ESHG Recommendations. Eur J Hum Genet 17 (6): 711-9, 2009. [PUBMED Abstract]
  79. Resta R, Biesecker BB, Bennett RL, et al.: A new definition of Genetic Counseling: National Society of Genetic Counselors' Task Force report. J Genet Couns 15 (2): 77-83, 2006. [PUBMED Abstract]
  80. National Research Council Committee for the Study of Inborn Errors of Metabolism: Genetic Screening Programs, Principles, and Research. Washington, D.C.: National Academy of Sciences, 1975.
  81. Tessaro I, Borstelmann N, Regan K, et al.: Genetic testing for susceptibility to breast cancer: findings from women's focus groups. J Womens Health 6 (3): 317-27, 1997. [PUBMED Abstract]
  82. Richards M: Families, kinship and genetics. In: Marteau T, Richards M, eds.: The Troubled Helix: Social and Psychological Implications of the New Human Genetics. Cambridge, England: Cambridge University Press, 1996, pp 249-273.
  83. Hallowell N, Statham H, Murton F: Women's understanding of their risk of developing breast/ovarian cancer before and after genetic counseling. J Genet Couns 7 (4): 345-64, 1998.
  84. Baum A, Friedman AL, Zakowski SG: Stress and genetic testing for disease risk. Health Psychol 16 (1): 8-19, 1997. [PUBMED Abstract]
  85. Peters JA, Stopfer JE: Role of the genetic counselor in familial cancer. Oncology (Huntingt) 10 (2): 159-66, 175; discussion 176-6, 178, 1996. [PUBMED Abstract]
  86. Richards M: Families, kinship and genetics. In: Marteau T, Richards M, eds.: The Troubled Helix: Social and Psychological Implications of the New Human Genetics. Cambridge, England: Cambridge University Press, 1996, pp 264-265.
  87. Croyle RT, Achilles JS, Lerman C: Psychologic aspects of cancer genetic testing: a research update for clinicians. Cancer 80 (3 Suppl): 569-75, 1997. [PUBMED Abstract]
  88. Kessler S: Psychological aspects of genetic counseling, X: advanced counseling techniques. J Genet Couns 6 (4): 379-92, 1997.
  89. van Dooren S, Rijnsburger AJ, Seynaeve C, et al.: Psychological distress and breast self-examination frequency in women at increased risk for hereditary or familial breast cancer. Community Genet 6 (4): 235-41, 2003. [PUBMED Abstract]
  90. Lerman C, Schwartz MD, Lin TH, et al.: The influence of psychological distress on use of genetic testing for cancer risk. J Consult Clin Psychol 65 (3): 414-20, 1997. [PUBMED Abstract]
  91. Shoda Y, Mischel W, Miller SM, et al.: Psychological interventions and genetic testing: facilitating informed decisions about BRCA1/2 cancer susceptibility. J Clin Psychol Med Settings 5 (1): 3-17, 1998.
  92. Patenaude AF: Genetic Testing for Cancer: Psychological Approaches for Helping Patients and Families. Washington, DC: American Psychological Association, 2005.
  93. Vadaparampil ST, Miree CA, Wilson C, et al.: Psychosocial and behavioral impact of genetic counseling and testing. Breast Dis 27: 97-108, 2006-2007. [PUBMED Abstract]
  94. Radloff LS: The CES-D scale: a self-report depression scale for research in the general population. Applied Psychological Measurement 1 (3): 385-401, 1977.
  95. McNair D, Lorr M, Droppelman L, et al.: Profile of Mood States. San Diego, Calif: Educational and Industrial Testing Service, 1971.
  96. Ford S, Lewis S, Fallowfield L: Psychological morbidity in newly referred patients with cancer. J Psychosom Res 39 (2): 193-202, 1995. [PUBMED Abstract]
  97. Derogatis LR, Melisaratos N: The Brief Symptom Inventory: an introductory report. Psychol Med 13 (3): 595-605, 1983. [PUBMED Abstract]
  98. Rolland JS: Families, Illness, and Disability: An Integrative Treatment Model. New York, NY: BasicBooks, 1994.
  99. Olsen S, Dudley-Brown S, McMullen P: Case for blending pedigrees, genograms and ecomaps: nursing's contribution to the 'big picture'. Nurs Health Sci 6 (4): 295-308, 2004. [PUBMED Abstract]
  100. Peters JA, Hoskins L, Prindiville S, et al.: Evolution of the colored eco-genetic relationship map (CEGRM) for assessing social functioning in women in hereditary breast-ovarian (HBOC) families. J Genet Couns 15 (6): 477-89, 2006. [PUBMED Abstract]
  101. Peters JA, Kenen R, Giusti R, et al.: Exploratory study of the feasibility and utility of the colored eco-genetic relationship map (CEGRM) in women at high genetic risk of developing breast cancer. Am J Med Genet A 130 (3): 258-64, 2004. [PUBMED Abstract]
  102. Hadley DW, Ashida S, Jenkins JF, et al.: Generation after generation: exploring the psychological impact of providing genetic services through a cascading approach. Genet Med 12 (12): 808-15, 2010. [PUBMED Abstract]
  103. Lerman C, Narod S, Schulman K, et al.: BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 275 (24): 1885-92, 1996. [PUBMED Abstract]
  104. Lerman C, Biesecker B, Benkendorf JL, et al.: Controlled trial of pretest education approaches to enhance informed decision-making for BRCA1 gene testing. J Natl Cancer Inst 89 (2): 148-57, 1997. [PUBMED Abstract]
  105. Bluman LG, Rimer BK, Berry DA, et al.: Attitudes, knowledge, and risk perceptions of women with breast and/or ovarian cancer considering testing for BRCA1 and BRCA2. J Clin Oncol 17 (3): 1040-6, 1999. [PUBMED Abstract]
  106. van Dijk S, Otten W, Timmermans DR, et al.: What's the message? Interpretation of an uninformative BRCA1/2 test result for women at risk of familial breast cancer. Genet Med 7 (4): 239-45, 2005. [PUBMED Abstract]
  107. Dorval M, Patenaude AF, Schneider KA, et al.: Anticipated versus actual emotional reactions to disclosure of results of genetic tests for cancer susceptibility: findings from p53 and BRCA1 testing programs. J Clin Oncol 18 (10): 2135-42, 2000. [PUBMED Abstract]
  108. Bennett RL: The Practical Guide to the Genetic Family History. New York, NY: Wiley-Liss, 1999.
  109. Forrest LE, Burke J, Bacic S, et al.: Increased genetic counseling support improves communication of genetic information in families. Genet Med 10 (3): 167-72, 2008. [PUBMED Abstract]
  110. Hamann HA, Smith TW, Smith KR, et al.: Interpersonal responses among sibling dyads tested for BRCA1/BRCA2 gene mutations. Health Psychol 27 (1): 100-9, 2008. [PUBMED Abstract]

Ethical, Legal, and Social Implications

Having an understanding of the ethical, legal, and social implications (ELSI) regarding cancer genetic testing may influence the clinician’s response to the complex questions and issues that may arise during the process of risk assessment and counseling. This section discusses biomedical ethics codes, legal and social issues relevant to privacy, and fair use in the interpretation of genetic information. In order to integrate the different perspectives of bioethics, law, and psychosocial influences, case scenarios are offered to illustrate dilemmas encountered in the clinical setting. (Refer to the Determining the Test to Be Used section of this summary for more information about the regulation of genetic tests.)

Bioethical Issues in Cancer Genetic Testing

Bioethical tenets can guide health care providers in dealing with the complex issues surrounding predictive testing for hereditary cancer. The tenets of beneficence, nonmaleficence, autonomy, and justice are part of a framework needed to balance the complex and potentially conflicting factors surrounding a clinician’s role in respecting privacy, confidentiality and fair use of genetic information obtained from cancer genetic testing.

Beneficence

The concept of beneficence dictates that the primary goal of medical care is to provide benefit through appropriate health care.[1] In the field of oncology, this translates into using early detection and effective treatment protocols to improve outcomes. Providing beneficent care may go beyond medical outcomes of treatment to encompass the patient’s life circumstances, expectations, and values.[1] Consideration of the patient’s psychological and emotional ability to handle the testing and results disclosure process can help avoid doing harm.[2] (Refer to the Psychological Impact of Genetic Testing/Test Results on the Individual section of this summary for more information.)

Nonmaleficence

Nonmaleficence is the bioethical code that directs health care providers to do no harm, inclusive of physical and emotional harm, and acknowledges that medical care involves risks and benefits.[1] Particular to the field of oncology, adherence to this construct includes taking measures to minimize the adverse effects of cancer prevention, treatment, and control. This may encompass taking precautionary measures to prevent inadvertent disclosure of sensitive information.[2]

Autonomy

Autonomous decision making respects individual preferences by incorporating informed consent and education.[1] Individuals have the right to be informed about the risks and benefits of genetic testing and to freely choose or decline testing for themselves. Additionally, it is beneficial to consider the sociocultural context and family dynamics to ensure medical decision making takes places without coercion or interference.[1]

Justice

Justice refers to the equitable distribution of the benefits and risks of health care.[1] A goal in oncology is ensuring access to cancer genetic services. The availability of predictive genetic testing should not be dependent on ethnic background, geographical location, or ability to pay. Genetic discrimination should not be a result of predictive testing.[2] Equitable distribution balances individual rights with responsibilities of community membership.[1]

Privacy and Confidentiality: Disclosure of Patient’s Genetic Information

A strong provider-patient relationship is founded on respect for the patient’s privacy and confidentiality; therefore, protecting the patient’s personal information from third parties is key to building trust.[2,3] Predictive testing for cancer susceptibility presents a challenge because of the hereditary nature of the diseases being tested and the implications of genetic risk for family members. Physicians are faced with a duty to warn or to act to prevent foreseeable harm.[4] One practical suggestion for facilitating family-based communication is providing patients with education and information materials to facilitate disease susceptibility discussions with family members.[1] The next section discusses the legal, legislative, and ethical basis for balancing patient confidentiality with duty to warn.

Disclosure in research

Privacy and confidentiality also applies to research, such as population screening for genetic diseases. The U.S. Department of Health and Human Services authorizes the use of Certificates of Confidentiality to researchers.[5] This certificate, issued by the National Institutes of Health, protects the researcher from having to reveal the identity of any research subject “in any Federal, State, or local civil, criminal, administrative, legislative, or other proceedings.” The protections offered by the certificate of confidentiality are limited to personally identifiable information collected beginning on the date of issuance and ending on the expiration date, which matches the date of study completion. The NIH Office of Extramural Research policy and guidance on Certificates of Confidentiality notes that any personally identifiable information collected during that time interval is protected in perpetuity. In regard to family-based recruitment strategies, the Cancer Genetics Network Bioethics Committee assembled a group of experts to develop recommendations for researchers to use in approaching family members.[6] Due to the wide spectrum of research strategies, there are different levels of concern. Essential to family-based recruitment strategies is informing potential research participants how their personal information was obtained by the researcher, why the researcher is approaching them, what the researcher knows about them, and for what purpose the information will be used, whether or not they decide to participate.[6]

“Duty to warn”: Legal proceedings, federal/state legislation, and recommendations of professional organizations

“Duty to warn” requires balancing the bioethical constructs of beneficence and autonomy with other factors such as case proceedings, legislation, and professional societies’ recommendations. As of September 2008, the National Council of State Legislatures lists the states that have legislation requiring consent to disclose genetic information. The definition of "genetic information" can vary depending on the legal case and the language used in state and federal legislation, and generally includes genetic testing and family history information; however, the definition generally does not apply to current diagnoses. Genetic diagnosis can be done through direct genetic tests for disorders linked to a specific gene and indirect genetic tests for disorders in which the specific genes are not known or there are multiple different genes involved (genetic heterogeneity).[7] There are four state case laws that apply to duty to warn.[8] Two cases deal directly with testing for hereditary cancer predisposition syndromes; one case deals with a psychotherapist's duty to warn a relative of imminent threat, and another with genetic testing as a tool for reproductive decisions. Table 4 summarizes the cases.

Table 4. State Case Laws That Apply to Duty to Warn
State Case Law Description Summary
Tarasoff versus Regents of the University of California [9,10] Establishes moral duty to warn family members of risks unknown to them In 1976, the California court judged that breach of confidentiality would have been justified in order to warn of a foreseeable and serious harm to an identifiable individual.
Distinct from genetic risk since the pathogenic variant is already present (or absent) in family members
Pate versus Threlkel [8,11,12] Duty to warn family members of hereditary risk of cancer is satisfied by telling the patient to tell his or her family In 1995, the Florida court judged that a physician had a duty to warn the patient that her children were at risk of developing thyroid cancer because the disease could have been detected and cured at an earlier stage.
Safer versus Estate of Pack [8,13] Physician must take reasonable steps to warn family members of hereditary risk disease In 1996, a New Jersey appellate court defined a physician’s duty to warn immediate family members of risk of colon cancer; however, the court ruled in favor of the doctor because the patient had undergone rectal screening as a child, which indicated that she had been warned of the risk.
Molloy versus Meier [8,14] Physician’s duty regarding genetic testing and diagnosis of foreseeable disease risk extends beyond the patient to biological parents In 2004, a Minnesota Supreme Court held that the physician failed to breach confidentiality to warn of hereditary disease risk because he did not inform parents of the diagnosis of fragile X syndrome in their first child. The parents state that this information would have influenced their reproductive decisions.

At the federal level, there are strict nondisclosure policies governing private health information.[8] The Standards for Privacy of Individually Identifiable Health Information (Privacy Rule), which summarizes the Health Insurance Portability and Accountability Act (HIPAA) of 1996, finds it permissible to disclose health information without consent when the public interest is at risk;[15,16] therefore, under certain conditions, there are exceptions to the nondisclosure policy include the following:

  1. There is serious or imminent threat to the health or safety of a person or the public.
  2. The threat constitutes an imminent, serious threat to an identifiable third party.
  3. The physician has the capacity to avert significant harm.

Professional societies and government advisory agencies have published their different positions and recommendations on communication between a physician and a patient's relatives in regard to disclosure of genetic disease.[4,8,17]

The Council on Ethical and Judicial Affairs of the American Medical Association (AMA) and the American Society of Clinical Oncology (ASCO) [18,19] encourage discussing the importance of patients sharing genetic information with family members.[4] Specifically, the Council on Ethical and Judicial Affairs of the American Medical Association states that “Physicians …should identify circumstances under which they would expect patients to notify biological relatives of the availability of information related to risk of disease…(and) physicians should make themselves available to assist patients in communicating with relatives to discuss opportunities for counseling and testing, as appropriate.” ASCO’s position is that providers “should remind patients of the importance of communicating test results to family members… ASCO believes that the cancer care provider’s obligations (if any) to at-risk relatives are best fulfilled by communication of familial risk to the person undergoing testing, emphasizing the importance of sharing this information with family members so that they may also benefit.”[18] These organizations recommend that family members disclose genetic information.

The National Society of Genetic Counselors [20] and the International Society of Nurses in Genetics [21] support the release of any genetic information upon request to third parties including relatives but only with the patient's consent.[4] One of the tenets of genetic counseling is to maintain information received from clients as confidential, unless released by the client or consent for disclosure is provided as required by law.[4,20]

Similar to the Privacy Rule, the U.S. Bioethics Commission,[22] American Society of Human Genetics,[23] and National Human Genome Research Institute (NHGRI) recommend the following guidelines to identify exceptional circumstances under which it is ethically acceptable to breach confidentiality.[4,8]

  1. There is a high likelihood of harm if the relative is not warned.[4,22,23]
  2. The patient, despite encouragement, refuses to inform family members.[4,22,23]
  3. The relative is identifiable.[23]
  4. The harm of nondisclosure is greater than the harm of disclosure.[23]
  5. Current medical technology renders the disease preventable, treatable, or manageable.[23]
  6. Only the information necessary to prevent harm is released.[4,24]
  7. There is no other reasonable way to avert harm.[4]

At an international level, the World Health Organization and World Medical Association have similar guidelines.[4] Additionally, Australia, Canada, Germany, Japan, the Netherlands, and the United Kingdom have guidelines supporting the disclosure of genetic information to relatives under similar exceptional circumstances.[4]

Employment and Insurance Discrimination

Genetic information obtained from genetic susceptibility tests may have medical, economic, and psychosocial implications for the individual tested and his or her family members. Employment and insurance discrimination are common concerns for individuals considering genetic testing. A review of ethical controversies in cancer genetics clinics included a phone interview of over 300 members of genetics support groups; 13% of the study participants reported being denied or dismissed from a job, and 22% reported being refused life insurance because of a genetic disorder in the family.[10,12,25]

Few empiric studies have documented the occurrence of insurance, employment, or other discrimination based on genetic test results for hereditary cancer syndromes. A study published in 2000 (8 years prior to the passage of the federal Genetic Information Nondiscrimination Act [GINA]) concluded that the use of information regarding presymptomatic genetic testing in health insurance underwriting decisions rarely, if ever, occurred either before or after the passage of state laws prohibiting such discrimination.[26] Findings in this study were based on interviews with 29 genetic counselors, 5 patient advocates, 12 insurance regulators, 35 representatives of insurers, and 30 insurance agents.

In a smaller study of 47 unaffected BRCA or mismatch repair pathogenic variant carriers, a few instances of denial or limitation of life and health insurance benefits were reported following genetic testing; however, it was not possible to determine whether these adverse effects were directly related to the results of genetic testing. Nonetheless, a subset of carriers of pathogenic variants reported that they paid for genetic testing out-of-pocket to avoid possible insurance discrimination (32%), had relatives who did not have genetic testing because of discrimination concerns (13%), and expressed reluctance to seek new job opportunities because of concerns about insurance coverage (13%).[27]

A 2007 survey of members of the National Society of Genetic Counselors' (NSGC) Cancer Special Interest Group found that 94% perceived the risk of genetic discrimination to be low, very low, or theoretical.[28] Most reported that they felt very or somewhat confident in the ability of U.S. federal and state laws (64% and 70%, respectively) to protect against genetic discrimination for cancer predisposition testing. Most disagreed that there are problems with health insurance as a result of having genetic testing, either for a person with (93%) or without (79%) a cancer diagnosis. The results of this study suggest that genetic counselors, who are on the forefront or providing risk assessment and counseling for hereditary cancers, may perceive the risk of genetic discrimination to be low and believe that existing state and federal laws offer adequate protection. Nonetheless, 35% of the NSGC sample agreed that patients may decline genetic testing for hereditary cancer risk because of concerns about health insurance discrimination. In addition, all respondents reported discussing genetic discrimination with some proportion of their patients, and 87% reported that they offer reassuring information about genetic discrimination to their patients.

Public awareness of GINA and its protections is limited. In a multistate survey conducted in 2010, more than 80% of respondents indicated that they were unaware of the law.[29] In a 2014 survey of 1,479 U.S. adults, 79% indicated that they were unaware of the law.[30] Of those who were aware of GINA, 44% knew that it protected against health insurance and 33% knew it protected against employment discrimination; 23% incorrectly believed the law protected against life, disability, and long-term insurance discrimination. After reading a description of GINA, 30% of respondents indicated that they were actually more concerned about discrimination [note: The denominator for the latter finding is uncertain]. Although genetic testing has increased since the passage of the law, relatively few cases of discrimination in which GINA’s authority can be tested have been reported.[30]

(Refer to the Informed Consent and Exploration of potential risks, benefits, burdens, and limitations of genetic susceptibility testing subsections of this summary for more information about discrimination issues related to cancer genetics services.)

Legal proceedings, federal/state legislation, and recommendations of professional organizations

A legal case example at the federal district court level involves the Burlington Northern Santa Fe Railroad. The U.S. Equal Employment and Opportunities Commission requested that Burlington Northern Santa Fe Railroad not be allowed to use medical information obtained from genetic tests for employment decisions.[24]

In the last 15 years, state and federal legislation statutes have been developed to prevent the use of genetic information for employment practices, such as hiring, promotion, and salary decisions; and insurance policies, including life and health coverage, by employers, schools, government agencies, and insurers.[12] According to Executive Order 13145, federal departments and agencies are prohibited from discriminating against employees on the basis of genetic test results or information about a request for genetic testing services.[24] Employers and insurers are prohibited from intentionally lowering policy rates by using practices such as screening for individuals who are at risk of becoming ill or dying due to genetic disease susceptibility, such as cancer.[24] Federal laws, including GINA, do not cover employer-provided life and disability; however, some states do have legislation addressing the use of genetic information for life and disability policies. The National Conference of State Legislatures (NCSL) [31,32] summarized current health legislation of the U.S. Congress. Examples of relevant legislation regarding genetic information include, GINA, HIPAA, Americans with Disabilities Act (ADA), and Employee Retirement Income Security Act (ERISA).

Table 5. Comparison of Federal Legislation Addressing Genetic Coverage, Limitations, and Protections
Law Coverage Limitations Protect All Americans
Adapted from Leib et al.[33]
Civil Rights Act of 1964 Employment only Does not apply to health insurance Yes
Applies in instances of discrimination based on genetic information if associated with race or ethnic groups Strong association with a racial or ethnic group for hereditary cancers is rare
Americans with Disabilities Act of 1990 Disabilities associated with manifesting genetic information Does not apply to health insurance Yes
Health Insurance Portability and Accountability Act of 1996 Group health insurance plans Does not stop insurers from requiring genetic tests Yes
Genetic information is not defined
Forbids excluding an individual in a group health plan due to genetic information Genetic information can be used for plan underwriting
Forbids premium increases for different group plan members Disclosure of genetic information is not restricted
Preexisting conditions can not include predictive genetic information Does not apply to individual health plans, unless covered by the portability provision
Executive Order 13145 of 2000 Forbids Federal employee workplace genetic discrimination Does not apply to health insurance No; excludes members of the United States military and anyone who is NOT a federal employee
Only applies to Federal employees
Genetic Information Nondiscrimination Act of 2008 (GINA) (Enacted in 2009) Forbids genetic discrimination in the workplace and in health insurance Civil suit is restricted to only those who have had all administrative remedies exhausted No; excludes members of the United States military, veterans obtaining health care through the Veteran’s Administration, and the Indian Health Service
Genetic information broadly defined
Specific to group and individual insurance plans
Forbids use of genetic information in underwriting
Forbids requiring genetic testing by employers and insurers Does not cover life, disability, and long-term care insurance
Genetic Information Nondiscrimination Act 2008

GINA 2008 protects the provision of health insurance and employment against discrimination based on genetic information as follows:

  • Prohibits access to individuals’ personal genetic information by insurance companies and by employers.[34]
  • Prohibits insurance companies from requesting that applicants for group or individual health coverage plans be subjected to genetic testing or screening and prohibits them from discriminating against health plan applicants based on individual genetic information.[34]
  • Prohibits employers from using genetic information to refuse employment, and prohibits them from collecting employees’ personal genetic information without their explicit consent.[34]
  • Prohibits employment agencies from failing or refusing to refer a candidate on the basis of genetic information.[35]
  • Prohibits labor organizations from refusing membership based on a member's genetic make-up.[35]
  • Does not mandate coverage for medical tests or treatments.[36]
  • Does not prohibit medical underwriting based on current health status.[36]
  • Does not limit a treating health provider, including those employed by or affiliated with health plans, from requesting or notifying individuals about genetic tests.[37]
  • Does not prohibit occupational testing for toxic monitoring programs, employer-sponsored wellness programs, administration of federal and state family and medical leave laws, and certain cases of inadvertent acquisition of genetic information.[38]

GINA amends and/or extends coverage of HIPAA, ADA, and ERISA by including genetic information under medical privacy and confidentiality legislation and employment and insurance determinations.[31] Additionally, with the passage of GINA, researchers and clinicians can encourage participation in clinical trials and appropriate genetic testing knowing that there are federal protections against discrimination based on the results of genetic testing. GINA established the minimum protection level that must be met in all states. However, for states with more robust legislation in place, GINA does not weaken existing protections provided by state law.

However, GINA has several limitations.

  1. GINA does not apply to members of the United States military, to veterans obtaining health care through the Veteran’s Administration, or to the Indian Health Service because the laws amended by GINA do not apply to these groups and programs.
  2. The legislation does not apply to life insurance, long-term care insurance, or disability insurance. Even though GINA does not provide protection for employer-provided disability and life insurance, some states do encompass these arenas in addition to employment, genetic privacy, health insurance, health insurance enforcement, life, disability, and long term care. NHGRI's Genome Status and Legislation Database provides a searchable listing of state statutes and bills related to the following topics: direct-to-consumer genetic testing, employment and insurance nondiscrimination, health insurance coverage, privacy, research, and the use of residual newborn screening specimens.
  3. GINA’s employment provisions generally do not apply to employers with fewer than 15 employees.[36]

A study conducted between 2009 and 2010 via a survey posted on the Facing Our Risk of Cancer Empowered (FORCE) website provides insight into consumers' perspectives regarding insurance discrimination based on genetic test results after the passage of GINA. Of the 1,669 participants (69% of whom previously received genetic testing), 53% indicated that they had heard about insurance discrimination based on genetic test results. More than half the sample (54%) reported that they had not heard about GINA before the survey. After being provided with a brief description of GINA as part of the survey process, 60% (n = 886) reported a change in their feelings about genetic testing, with the majority (573 of 886 participants) indicating less concern about health insurance discrimination. Finally, when asked whom they would contact regarding questions about GINA, 38% indicated their health care provider.[39]

Exception to protections against employment and insurance discrimination: Active duty military personnel

GINA and other state and federal protections do not extend to genetic testing of active duty military personnel or genetic information obtained from active duty military personnel.[40] In the military, genetic testing provides medical information that is to be used to protect military personnel from harmful duty or other exposures that could stimulate or aggravate a health problem. For example, use of certain antimalaria medication in individuals with glucose 6-phosphate dehydrogenase deficiency can result in red blood cell rupture. Therefore, some genetic information is critical for maintaining the health and safety of military personnel, given the possible stressful occupational environments they face. In addition, all military personnel provide a DNA sample to be maintained in a repository that can be used for identification purposes.[41]

Results of genetic tests for disease predisposition could influence military eligibility for new enlistments, and for current military personnel, genetic test results could influence worldwide eligibility, assignments, and promotions. For example, a young woman found to carry a BRCA pathogenic variant may not be considered eligible for deployment for 12-15 months because access to recommended health care may not be easily accessible, such as breast MRI, a recommended screening modality for carriers of BRCA pathogenic variants. Active duty military personnel with less than eight years of active duty service are especially vulnerable in the event they become disabled and must go before the medical board to establish benefit eligibility.

In 2006, Department of Defense Instruction Number 1332.38 (DODINST 1332.38) redefined preexisting condition as a result of two cases brought by service members who each had a hereditary condition that presented later in their military careers. The disability instructions state that any injury or disease discovered after a service member enters active duty—with the exception of congenital and hereditary conditions—is presumed to have been incurred in the line of duty. Any hereditary and/or genetic disease shall be presumed to have been incurred prior to entry into active duty. However, DODINST 1332.38 further states that any aggravation of that disease, incurred in the line of duty, beyond that determined to be due to natural progression, shall be deemed service aggravated. As a result of these two cases, the 8-year active duty service limit was established. This means that after 8 or more years of military service, the natural progression of a genetic condition would be deemed aggravated by military service. Therefore, until late 2008, the presence of a congenital or hereditary condition would not be considered a preexisting condition in disability decision making for those with 8 or more years of service.

In October 2008, in response to the National Defense Authorization Act of 2008 (NDAA) Title XVI: “Wounded Warrior Matters,” a policy memorandum was issued providing supplemental and clarifying guidance on implementing disability-related provisions, including new language related to hereditary or genetic diseases. The policy memorandum states, “Any hereditary or genetic disease shall be evaluated to determine whether clear and unmistakable evidence demonstrates that the disability existed before the Service member’s entrance on active duty and was not aggravated by military service. However, even if the conclusion is that the disability was incurred prior to entry on active duty, any aggravation of that disease, incurred while the member is entitled to basic pay, beyond that determined to be due to natural progression shall be determined to be service aggravated.” The interpretation of this policy is uncertain at this time.[41]

Case scenarios involving ELSI issues in cancer genetic testing

There are multiple psychosocial, ethical, and legal issues to consider in cancer genetic testing. Genetic tests for germline pathogenic variants have social and family implications. In addition to prevention and surveillance options, genetic testing should be offered in conjunction with genetic education and counseling.[18,19] A comprehensive strategy for dealing with ethical dilemmas can incorporate a shared approach to decision making, including open discussion, planning, and involvement of the family.[5] To integrate the different perspectives of bioethics, law, and psychosocial influences, the following scenarios can help health care providers become familiar with commonly encountered dilemmas; it is imperative, however, that the clinician evaluate each patient and his or her situation on a case-by-case basis. These case scenarios were adopted from “Counseling about Cancer: Strategies for Genetic Counseling;” the in-depth case examples are extensively discussed in the original text.[2]

Duty to warn versus privacy

A patient with known family history of breast cancer is interested in testing for BRCA1 and BRCA2 pathogenic variant. In reviewing her family history, the health care provider realizes that the patient is not aware of an additional rare but hereditary cancer pathogenic variant in a second-degree relative, which the health center tested and confirmed in the past. After talking with her family, the patient is unable to confirm the details of the second hereditary cancer pathogenic variant and again expresses interest in BRCA1/2 testing. Does the health care provider have a “duty to warn” the patient of the unknown cancer susceptibility gene in the family, at the risk of disclosing private patient information? The following issues are important to consider in resolving this case.

  1. Preserving the confidentiality of the relative and informing the patient of her cancer risk are both important goals. In general, the health care professional has a “Duty to warn” when there is a high likelihood of harm if not warned, the person at risk is identifiable, the harm of nondisclosure is greater than disclosure, and only the information necessary to prevent harm is released. (Refer to the Privacy and Confidentiality: Disclosure of Patient’s Genetic Information section of this summary for more information.)
  2. It is possible that the benefit outweighs the harm of informing the patient of the second cancer syndrome because the monitoring and management of the rare cancer are different from guidelines for the general population. Additionally both parties are identifiable. An option is to contact the relative for permission to disclose the genetic test result to the patient in question.
  3. If it is not possible to obtain permission to disclose, it is possible to inform the patient that she meets clinical criteria for the hereditary cancer syndrome without releasing specific information about the genetic test results of the relative.
Patient’s right to know versus family member’s autonomy

A patient with a family history of a hereditary cancer is interested in predictive genetic testing and convinces an affected family member, who initially expresses unwillingness, to be tested in order to establish the familial pathogenic variant. In this scenario, the surviving family member admits to feeling pressured into consenting for genetic testing. Both the patient and the affected family member are patients. What takes precedence—the patient’s right to know or the family member’s autonomy? The following issues are important to consider in resolving this case.

  1. Explore, with the patient, alternatives to testing that do not involve the participation of the unwilling family member, such as testing stored tissue of a deceased relative. (Refer to the Value of Testing an Affected Family Member First section of this summary for more information).
  2. If the patient does not want to consider other options and the family member has agreed to be tested without coercion or interference, inform the family member of the implications of the test results, including risks and benefits, and assess her emotional well-being prior to testing.[20] (Refer to the Informed Consent section of this summary for more information.)
Right to know versus right not to know

A hereditary cancer syndrome has been identified in a family. Within that family, an adult child wants a cancer susceptibility test that her parent declined, and one identical twin wants testing but the other does not. Even though the uninterested parties have declined testing and do not want to know the results, it is possible that testing one relative can disclose results for the other family members. Do the rights of the family members interested in predictive testing take precedence over the rights of the relatives who do not want to know? The following issues are important to consider in resolving this case.

  1. In hereditary cancer syndromes, an individual’s right to know takes precedence over an individual’s right not to know especially if there are early detection and prevention strategies to reduce the likelihood of morbidity and mortality.
  2. Since the family has a documented pathogenic variant, standard of care recommendations include guidelines for screening and monitoring. In the event that testing is not done, it is important to take “reasonable steps” to guarantee immediate family members are warned of the hereditary cancer risk. (Refer to the Privacy and Confidentiality: Disclosure of Patient’s Genetic Information section of this summary for more information.)
  3. Pretest and posttest discussions can include the possibility of medical, psychological, and social impact on family members and strategies on how to lessen any negative impact. The patient should honor the wishes of relatives who request not to know and attempt to keep the results secret.[20]
Beneficence versus paternalism

A psychological assessment of a patient interested in predictive testing for an autosomal dominant cancer reveals a history of depression and suicidal attempts. The health care provider is considering denying or deferring testing because of concerns for the patient’s emotional well-being even though the patient refuses a referral to a psychologist because he reports feeling emotionally stable. Is deferring or denying predictive genetic testing a beneficent gesture or an act of paternalism? The following issues are important to consider in resolving this case.

  1. Despite the patient’s refusal to speak with a psychologist, the health care provider can discuss the details of the case with a mental health professional to determine suicidal risk. (Refer to the Psychological Impact of Genetic Information/Test Results on the Individual section of this summary for more information.)
  2. If there is risk of psychosocial disturbances because of test results, it is possible to defer testing. Conditions under which testing can resume are explained to the patient. For example, the NSGC Code of Ethics recommends that clients be referred to other qualified professionals when the patient requires additional services.[20]
  3. Denying a test does not seem justifiable under any circumstances because it implies that the client will never be able to undergo testing.

Professional guidelines and other resources

(Refer to the Genetic Resources section of the PDQ Cancer Genetics Overview summary for more information about the ELSI of genetic testing and counseling.)

References
  1. Burke W, Press N: Genetics as a tool to improve cancer outcomes: ethics and policy. Nat Rev Cancer 6 (6): 476-82, 2006. [PUBMED Abstract]
  2. Schneider K: The ethical issues. In: Schneider KA: Counseling About Cancer: Strategies for Genetic Counseling. 2nd ed. New York, NY: Wiley-Liss, 2002, pp 291-312.
  3. Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: John Wiley and Sons, 1998.
  4. Godard B, Hurlimann T, Letendre M, et al.: Guidelines for disclosing genetic information to family members: from development to use. Fam Cancer 5 (1): 103-16, 2006. [PUBMED Abstract]
  5. Offit K: Psychological, ethical, and legal issues in cancer risk counseling. In: Offit K: Clinical Cancer Genetics: Risk Counseling and Management. New York, NY: John Wiley and Sons, 1998, pp 287-315.
  6. Beskow LM, Botkin JR, Daly M, et al.: Ethical issues in identifying and recruiting participants for familial genetic research. Am J Med Genet A 130A (4): 424-31, 2004. [PUBMED Abstract]
  7. Tantravahi U, Wheeler P: Molecular genetic testing for prenatal diagnosis. Clin Lab Med 23 (2): 481-502, 2003. [PUBMED Abstract]
  8. Offit K, Groeger E, Turner S, et al.: The "duty to warn" a patient's family members about hereditary disease risks. JAMA 292 (12): 1469-73, 2004. [PUBMED Abstract]
  9. California requires psychiatrists to warn about dangerous patients - Tarasoff v. Regents of University of California, 17 Cal. 3d 425, 551 P.2d 334, 131 Cal. Rptr. 14 (Cal. 1976). 1976. Also available online. Last accessed April 21, 2016.
  10. Harris M, Winship I, Spriggs M: Controversies and ethical issues in cancer-genetics clinics. Lancet Oncol 6 (5): 301-10, 2005. [PUBMED Abstract]
  11. Pate v. Threlkel, 661 So. 2d 278 (Florida 1995). 1995. Also available online. Last accessed April 21, 2016.
  12. Sankar P: Genetic privacy. Annu Rev Med 54: 393-407, 2003. [PUBMED Abstract]
  13. Safer v. Estate of Pack, 677 A2d 1188 (NJ App), appeal denied, 683 A2d 1163 (NJ 1996). 1996. Also available online. Last accessed April 21, 2016.
  14. Molloy v. Meier, Nos. C9-02-1821, C2-02-1837 (Minn 2004). 2004. Also available online. Last accessed April 21, 2016.
  15. Health Insurance Portability and Accountability Act of 1996, Public Law 104-191, 104th Congress. Washington, DC: 1996. Also available online. Last accessed April 21, 2016.
  16. US Department of Health and Human Services: OCR Privacy Brief: Summary of the HIPAA Privacy Rule. Washington, DC: US Department of Health and Human Services, 2002. Also available online. Last accessed April 21, 2016.
  17. Gordijn B: Genetic diagnosis, confidentiality and counseling: an ethics committee's potential deliberations about the do's and don'ts. HEC Forum 19 (4): 303-12, 2007. [PUBMED Abstract]
  18. Robson ME, Storm CD, Weitzel J, et al.: American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol 28 (5): 893-901, 2010. [PUBMED Abstract]
  19. Robson ME, Bradbury AR, Arun B, et al.: American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol 33 (31): 3660-7, 2015. [PUBMED Abstract]
  20. National Society of Genetic Counselors: National Society of Genetic Counselors Code of Ethics. Chicago, Il: National Society of Genetic Counselors, 2006. Also available online. Last accessed April 21, 2016.
  21. International Society of Nurses in Genetics: Position Statements: Privacy and Confidentiality of Genetic Information: The Role of the Nurse. Pittsburgh, Pa: International Society of Nurses in Genetics, 2010. Also available online. Last accessed April 21, 2016.
  22. US President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research: Screening and Counseling for Genetic Conditions: The Ethical, Social, and Legal Implications of Genetic Screening, Counseling, and Education Programs. Washington, DC: Government Printing Office, 1983. Also available online. Last accessed April 21, 2016.
  23. ASHG statement. Professional disclosure of familial genetic information. The American Society of Human Genetics Social Issues Subcommittee on Familial Disclosure. Am J Hum Genet 62 (2): 474-83, 1998. [PUBMED Abstract]
  24. Lowrey KM: Legal and ethical issues in cancer genetics nursing. Semin Oncol Nurs 20 (3): 203-8, 2004. [PUBMED Abstract]
  25. Lapham EV, Kozma C, Weiss JO: Genetic discrimination: perspectives of consumers. Science 274 (5287): 621-4, 1996. [PUBMED Abstract]
  26. Hall MA, Rich SS: Laws restricting health insurers' use of genetic information: impact on genetic discrimination. Am J Hum Genet 66 (1): 293-307, 2000. [PUBMED Abstract]
  27. McKinnon W, Banks KC, Skelly J, et al.: Survey of unaffected BRCA and mismatch repair (MMR) mutation positive individuals. Fam Cancer 8 (4): 363-9, 2009. [PUBMED Abstract]
  28. Huizenga CR, Lowstuter K, Banks KC, et al.: Evolving perspectives on genetic discrimination in health insurance among health care providers. Fam Cancer 9 (2): 253-60, 2010. [PUBMED Abstract]
  29. Parkman AA, Foland J, Anderson B, et al.: Public awareness of genetic nondiscrimination laws in four states and perceived importance of life insurance protections. J Genet Couns 24 (3): 512-21, 2015. [PUBMED Abstract]
  30. Green RC, Lautenbach D, McGuire AL: GINA, genetic discrimination, and genomic medicine. N Engl J Med 372 (5): 397-9, 2015. [PUBMED Abstract]
  31. National Conference of State Legislatures: Summary: Selected Health Legislation 110th Congress. Washington, DC: National Conference of State Legislatures, 2008. Also available online. Last accessed April 21, 2016.
  32. National Human Genome Research Institute: National Human Genome Research Institute Genome Statute and Legislation Database. Bethesda, Md: National Human Genome Research Institute, 2008. Also available online. Last accessed April 21, 2016.
  33. Leib JR, Hoodfar E, Haidle JL, et al.: The new genetic privacy law: how GINA will affect patients seeking counseling and testing for inherited cancer risk. Community Oncology 5 (6): 351-4, 2008.
  34. American Society of Human Genetics: Genetic Scientists Applaud U.S. Senate Passage of the Genetic Information Nondiscrimination Act: American Society of Human Genetics Supports Important New Legislation [Press Release - April 25, 2008]. Bethesda, Md: American Society of Human Genetics, 2008. Also available online. Last accessed April 21, 2016.
  35. Asmonga D: Getting to know GINA. An overview of the Genetic Information Nondiscrimination Act. J AHIMA 79 (7): 18, 20, 22, 2008. [PUBMED Abstract]
  36. National Human Genome Research Institute: "GINA": The Genetic Information Nondiscrimination Act of 2008: Information for Researchers and Health Care Professionals. Bethesda, MD: National Human Genome Research Institute, 2009. Available online. Last accessed July 13, 2016.
  37. United States Department of Labor: FAQs on the Genetic Information Nondiscrimination Act. Washington, DC: United States Department of Labor, 2010. Available online. Last accessed April 21, 2016.
  38. U.S. Equal Employment Opportunity Commission: The Genetic Information Nondiscrimination Act of 2008. Washington, DC: U.S. Equal Employment Opportunity Commission, 2008. Available online. Last accessed April 21, 2016.
  39. Allain DC, Friedman S, Senter L: Consumer awareness and attitudes about insurance discrimination post enactment of the Genetic Information Nondiscrimination Act. Fam Cancer 11 (4): 637-44, 2012. [PUBMED Abstract]
  40. Hudson KL, Holohan MK, Collins FS: Keeping pace with the times--the Genetic Information Nondiscrimination Act of 2008. N Engl J Med 358 (25): 2661-3, 2008. [PUBMED Abstract]
  41. Baruch S, Hudson K: Civilian and military genetics: nondiscrimination policy in a post-GINA world. Am J Hum Genet 83 (4): 435-44, 2008. [PUBMED Abstract]

Changes to This Summary (11/22/2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Introduction

Added Weitzel et al. as reference 2.

Added as Gabai-Kapara et al. as reference 6.

Components of the Risk Assessment Process

Revised text to include a detailed, multifaceted assessment including family history and a review of genetic testing options to the list of items generally included in the cancer risk assessment and counseling process.

The Option of Genetic Testing

Added Insurance coverage as a new subsection.

This summary is written and maintained by the PDQ Cancer Genetics Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about cancer genetics risk assessment and counseling. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Cancer Genetics Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Cancer Genetics Risk Assessment and Counseling are:

  • Kathleen A. Calzone, PhD, RN, APNG, FAAN (National Cancer Institute)
  • Suzanne M. O'Neill, MS, PhD, CGC (Northwestern University)
  • Beth N. Peshkin, MS, CGC (Lombardi Comprehensive Cancer Center at Georgetown University Medical Center)
  • Susan K. Peterson, PhD, MPH (University of Texas, M.D. Anderson Cancer Center)
  • Deborah E. Tamura, MS, RN, APNG (National Cancer Institute)
  • Susan T. Vadaparampil, PhD, MPH (H. Lee Moffitt Cancer Center & Research Institute)
  • Catharine Wang, PhD, MSc (Boston University School of Public Health)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Cancer Genetics Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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The preferred citation for this PDQ summary is:

PDQ® Cancer Genetics Editorial Board. PDQ Cancer Genetics Risk Assessment and Counseling. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: http://www.cancer.gov/about-cancer/causes-prevention/genetics/risk-assessment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389258]

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  • Updated: November 22, 2016

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