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Genetic Testing for Inherited Cancer Susceptibility Syndromes

What is genetic testing?

Genetic testing looks for specific inherited changes (variants) in a person’s genes. Genetic variants can have harmful, beneficial, neutral (no effect), or unknown or uncertain effects on the risk of developing diseases. Harmful variants in some genes are known to be associated with an increased risk of developing cancer. These inherited variants are thought to contribute to about 5 to 10% of all cancers.

Cancer can sometimes appear to “run in families” even if it is not caused by an inherited variant. For example, a shared environment or lifestyle, such as tobacco use, can cause similar cancers to develop among family members. However, certain patterns that are seen in members of a family—such as the types of cancer that develop, other non-cancer conditions that are seen, and the ages at which cancer typically develops—may suggest the presence of an inherited susceptibility to cancer.

Genes involved in many of the known inherited cancer susceptibility syndromes have been identified. Testing whether someone carries a harmful variant in one of these genes can confirm whether a condition is, indeed, the result of an inherited syndrome. Genetic testing is also done to determine whether family members who have not (yet) developed a cancer have inherited the same variant as a family member who is known to carry a harmful (cancer susceptibility predisposing) variant.

A different type of genetic testing, called tumor DNA sequencing, is sometimes done to determine if cancer cells of people who have already gotten a cancer diagnosis have genetic changes that can be used to guide treatment. Although some of these cancer cell changes may be inherited, most occur randomly during a person’s lifetime. Genetic testing of tumor cells is addressed in the Biomarker Testing for Cancer Treatment page.

Does someone who inherits a cancer susceptibility variant always get cancer?

No. Even if a cancer susceptibility variant is present in a family, it does not necessarily mean that everyone who inherits the variant will develop cancer. Several factors influence whether a given person with the variant will actually develop cancer. One is the penetrance of the variant. When not all people who carry a variant go on to develop the disease associated with that variant, it is said to have incomplete or reduced penetrance. Hereditary cancer syndromes can also vary in their expressivity—that is, people who inherit the variant may vary in the extent to which they show signs and symptoms of the syndrome, including the development of associated cancers. Lifestyle factors and environmental risks can also influence disease expression.

What genetic tests are available for cancer risk assessment?

More than 50 hereditary cancer syndromes have been described; see the PDQ Cancer Genetics Overview for a list of familial cancer susceptibility syndromes. Most of these are caused by harmful variants that are inherited in an autosomal dominant fashion—that is, a single altered copy of the gene inherited from one parent is enough to increase a person’s chance of developing cancer. For most of these syndromes, genetic tests for harmful variants are available.

Tests are also available for several inherited genetic variants that are not associated with named syndromes but have been found to increase cancer risk. Examples include inherited variants in PALB2 (associated with increased risks of breast and pancreatic cancers), CHEK2 (breast and colorectal cancers), BRIP1 (ovarian cancer), and RAD51C and RAD51D (ovarian cancer).

Who should consider genetic testing for cancer risk?

People who are concerned about whether their family history puts them at risk for cancer should consult with a genetic counselor.

The features of a person’s personal or family medical history that, particularly in combination, may suggest a hereditary cancer syndrome include:

  • Cancer was diagnosed at an unusually young age
  • Several different types of cancer occurred in the same person
  • Cancer in both organs in a set of paired organs, such as both kidneys or both breasts
  • Several first-degree relatives (the parents, siblings, or children of an individual) have the same type of cancer (for example, a mother, daughter, and sisters with breast cancer); family members with breast or ovarian cancer; family members with colon cancer and endometrial cancer
  • Unusual cases of a specific cancer type (for example, breast cancer in a man)
  • The presence of birth defects that are known to be associated with inherited cancer syndromes, such as certain noncancerous (benign) skin growths and skeletal abnormalities associated with neurofibromatosis type 1.
  • Being a member of a racial or ethnic group that is known to have an increased risk of having a certain inherited cancer susceptibility syndrome and having one or more of the above features as well
  • Several family members with cancer

If a person is concerned that they may have an inherited cancer susceptibility syndrome in their family, it is generally recommended that, when possible, a family member with cancer have genetic counseling and testing first, to identify with more certainty if the cancer in the family is due to an inherited genetic variant. Genetic testing is often more informative if it can begin in a family member with a previous or current cancer diagnosis than in someone who has never had cancer.

If a person in the family has already been found to have an inherited cancer susceptibility syndrome, then any family members who could have inherited the variant should consider genetic testing, even if they have not (yet) had a cancer. Knowing about their risks may help them to prevent a future cancer.

What is the role of genetic counseling in genetic testing for a hereditary cancer syndrome?

Genetic counseling is generally recommended before any genetic testing for a hereditary cancer syndrome and may also be performed after the test, especially if a positive result is found and a person needs to learn more about the hereditary cancer predisposition syndrome they have been found to have. This counseling should be performed by a trained genetic counselor or other health care professional who is experienced in cancer genetics. Genetic counseling usually covers many aspects of the testing process, including:

  • A hereditary cancer risk assessment based on an individual’s personal and family medical history
  • Discussion of:
    • The appropriateness of genetic testing and potential harms and benefits of testing
    • The medical implications of positive, negative, and uncertain test results
    • The possibility that a test result might not be informative (that is, it might find a variant whose effect on cancer risk is not known)
    • The psychological risks and benefits of genetic test results
    • The risk of passing a variant to children
    • The impact of testing for the family
    • The best test to perform
  • Explanation of the specific test(s) that might be used and the technical accuracy of the test(s) and their interpretation

Genetic counseling may also include discussing recommendations for preventive care and screening with the patient, referring the patient to support groups and other information resources, and providing emotional support to the person receiving the results.

Learning about these issues is a key part of the informed consent process for genetic testing. Written informed consent is usually obtained before a genetic test is ordered. People give their consent by signing a form saying that they have been told about, and understand, the purpose of the test, its medical implications, its risks and benefits, possible alternatives to the test, and their privacy rights.

Unlike most other medical tests, genetic tests can reveal information not only about the person being tested but also about that person’s relatives. Family relationships can be affected when one member of a family discloses genetic test results that may have implications for other family members. Family members may have different opinions about how useful it is to learn whether they have a disease-related genetic variant. Health discussions may get complicated when some family members know their genetic status while other family members do not want to know. A conversation with genetics professionals may help family members better understand the complicated choices they may face.

How is genetic testing done?

Genetic tests are usually requested by a person’s genetic counselor, doctor, or other health care provider who has reviewed the individual’s person and family history. The genetic test options from which a health professional may select include those that look at a single gene and those that look for harmful variants in multiple genes at the same time. Tests of the latter type are called multigene (or panel) tests.

Testing is done on a small sample of bodily fluid or tissue—usually blood, but sometimes saliva, cells from inside the cheek, or skin cells. The sample is then sent to a laboratory that specializes in genetic testing. The laboratory returns the test results to the doctor or genetic counselor who requested the test. It usually takes several weeks or longer to get the test results.

Health insurance typically covers genetic counseling and many genetic tests, if they are considered medically necessary. A person considering genetic testing should discuss costs and health insurance coverage with their doctor and insurance company before being tested.

What do the results of genetic testing mean?

Genetic testing can give several possible results: positive, negative, true negative, uninformative negative, variant of uncertain significance, or benign (harmless) variant.

Positive result. A positive test result means that the laboratory found a genetic variant that is associated with an inherited cancer susceptibility syndrome. A positive result may:

  • For a person who has cancer, confirm that the cancer was likely due to an inherited genetic variant and help guide treatment choices
  • Indicate an increased risk of developing certain cancer(s) in the future and guide future management to lower that risk
  • Provide important information that can help other family members make decisions about their own health care, such as whether to have genetic testing to see if they have also inherited the variant.

 Also, people who have a positive test result that indicates that they have an increased risk of developing cancer in the future may be able to take steps to lower their risk of developing cancer or to find cancer earlier, including:

  • Being checked at a younger age or more often for signs of cancer
  • Reducing their cancer risk by taking medications or having surgery to remove “at-risk” tissue. (These approaches to risk reduction are options for only a few inherited cancer syndromes.)
  • Changing personal behaviors (like quitting smoking, getting more exercise, and eating a healthier diet) to reduce the risk of certain cancers
  • Getting help to guide decisions about fertility and pregnancy

Negative result. A negative test result means that the laboratory did not find the specific variant that the test was designed to detect. This result is most useful when a specific disease-causing variant is known to be present in a family. In such a case, a negative result can show that the tested family member has not inherited the variant that is present in their family and that this person therefore does not have the inherited cancer susceptibility syndrome tested for. Such a test result is called a true negative. A true negative result does not mean that there is no cancer risk, but rather that the risk is probably the same as the cancer risk in the general population.

When a person has a strong family history of cancer but the family has not been found to have a known variant associated with a hereditary cancer syndrome, a negative test result is classified as an uninformative negative (that is, it typically does not provide useful information).

In the case of a negative test result, it is important that the person’s doctors and genetic counselors ensure that that person is receiving appropriate cancer screening based on that person’s personal and family history and any other risk factors they may have. Even when the genetic testing is negative, some individuals may still benefit from increased cancer surveillance.

Variant of uncertain significance. If genetic testing shows a change that has not been previously associated with cancer, the person’s test result may report a variant of uncertain significance, or VUS. This result may be interpreted as uncertain, which is to say that the information does not help to clarify their risk and is typically not considered in making health care decisions.

Some gene variants may be reclassified as researchers learn more about variants linked to cancer. Most often, variants that were initially classified as variants of uncertain significance are reclassified as being benign (not clinically important), but sometimes a VUS may eventually be found to be associated with increased risks for cancer. Therefore, it is important for the person who is tested to keep in touch with the provider who performed the genetic testing to ensure that they receive updates if any new information on the variant is learned.

Benign variant. If the test reveals a genetic change that is common in the general population among people without cancer, the change is called a benign variant. Everyone has commonly occurring benign variants that are not associated with any increased risk of disease.

Genetic test results are based on the best scientific information available at the time of the testing. While unfortunately no testing can be 100% error free, most genetic testing is quite accurate. However, it is very important to have the genetic testing ordered by a provider knowledgeable in cancer genetics who can choose a reputable testing lab to ensure the most accurate test results possible.

Who has access to a person’s genetic test results?

Medical test results are normally included in a person’s medical records, particularly if a doctor or other health care provider has ordered the test or has been consulted about the test results. Therefore, people considering genetic testing must understand that their results may become known to other people or organizations that have legitimate, legal access to their medical records, such as their insurance company or employer, if their employer provides the patient’s health insurance as a benefit.

However, legal protections are in place to prevent genetic discrimination, which would occur if health insurance companies or employers were to treat people differently because they have a gene variant that increases their risk of a disease such as cancer or because they have a strong family history of a disease such as cancer.

In 2008, the Genetic Information Nondiscrimination Act (GINA) became federal law for all U.S. residents. GINA prohibits discrimination based on genetic information in determining health insurance eligibility or rates and suitability for employment. However, GINA does not cover members of the military, and it does not apply to life insurance, disability insurance, or long-term care insurance. Some states have additional genetic nondiscrimination legislation that addresses the possibility of discrimination in those contexts.

In addition, because a person’s genetic information is considered one kind of health information, it is covered by the Privacy Rule of the Health Information Portability and Accountability Act (HIPAA) of 1996. The Privacy Rule requires that health care providers and others with medical record access protect the privacy of health information, sets limits on the use and release of health records, and empowers people to control certain uses and sharing of their health-related information. Many states also have laws to protect patient privacy and limit the release of genetic and other health information. The National Human Genome Research Institute Genetic Discrimination page includes links to more information about GINA, HIPAA, and other legislation related to genetic discrimination in insurance or employment.

Can at-home or direct-to-consumer genetic tests be used to test for cancer risk?

An increasing number of companies offer at-home genetic testing, also known as direct-to-consumer (DTC) genetic testing. People collect a saliva sample or a mouth swab themselves and submit the sample through the mail. They learn about the test results on a secure website, by mail, or over the phone.

The genetic testing for cancer risk that is typically ordered by a doctor involves testing for inherited genetic variants that are associated with a high to moderate increased risk of cancer and are responsible for inherited cancer susceptibility syndromes. By contrast, DTC genetic testing for cancer risk often involves the analysis of common inherited genetic variants that, individually, are generally associated with only a minor increase in risk. Even when added together, all the known common variants associated with a particular cancer type account for only a small portion of a person’s risk of that cancer. Genetic tests based on these common variants have not yet been found to help patients and their care providers make health care decisions and, therefore, they are not a part of recommended clinical practice. 

Even when people have DTC genetic tests for gene variants that are known to be associated with inherited cancer susceptibility syndromes, there are potential risks and drawbacks to the use of DTC testing. For instance, some DTC genetic tests look for variants in the BRCA1 and BRCA2 genes that are associated with Hereditary Breast and Ovarian Cancer Syndrome (HBOC). However, this testing looks only for three specific variants out of the thousands that have been identified. Therefore, someone could have a negative result with this kind of test but still have a harmful BRCA1 or BRCA2 gene variant that was just not identified by that test. In particular, without guidance about the most appropriate genetic testing to do and interpretation of the genetic test results from a knowledgeable health care provider, people may experience unneeded anxiety or false reassurance, or they may make important decisions about medical treatment or care based on incomplete information.

DTC genetic testing also does not ensure the privacy of the test results. Companies’ disclosure policies are not always provided, or they may be difficult to find and understand. In addition, companies that provide DTC testing may not be subject to current state and federal privacy laws and regulations. It is generally recommended that people considering DTC genetic testing make sure that they have chosen a reputable company (i.e., one that fully and clearly discloses its privacy policy).

The U.S. Federal Trade Commission (FTC) has a fact sheet about at-home genetic tests that offers advice for people who are considering such a test. As part of its mission, FTC investigates complaints about false or misleading health claims in advertisements.

Genetics Home Reference, a consumer health website from the National Library of Medicine at the National Institutes of Health, has information about DTC genetic testing.

What are some of the benefits of genetic testing for inherited cancer susceptibility syndromes?

There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.

  • An informative negative test can provide the person with peace of mind that a harmful gene variant was not inherited.
  • A positive test result provides the person an opportunity to understand and, in some cases, manage their cancer risks.
  • For people who are already diagnosed with a cancer, results of genetic testing may help them make decisions about their treatment and understand their risk for other cancers.
  • Genetic testing provides an opportunity for family members to learn about their own cancer risks.

What are some of the possible harms of genetic testing for inherited cancer susceptibility syndromes?

Genetic testing can have potential emotional, social, and financial harms, including:

  • Psychological stress of learning that one has a genetic variant that increases cancer risk and having to decide whether to share those findings with blood relatives
  • An uninformative test results, such as a report of a variant of uncertain significance (VUS), increases uncertainty and may increase stress until results are clarified
  • Survivor guilt upon learning that one doesn’t have a harmful variant that is present on other members of the family
  • Cost of testing itself and additional follow-up testing, if not covered by insurance 
  • Privacy and discrimination issues
  • Incorrect or misleading information provided by DTC or clinical genetic testing

How are genetic tests regulated?

U.S. laboratories that perform health-related testing, including genetic testing, are regulated under the Clinical Laboratory Improvement Amendments (CLIA) program. Laboratories that are certified under CLIA are required to meet federal standards for quality, accuracy, and reliability of tests. All laboratories that do genetic testing and share results must be CLIA certified. However, CLIA certification only indicates that appropriate laboratory quality control standards are being followed; it does not guarantee that a genetic test being done by a laboratory is medically useful or properly interpreted. The National Human Genome Research Institute has more information available on its Regulation of Genetics Tests page.

What research is being done to improve genetic testing for cancer?

Research is ongoing to find better ways to detect, treat, and prevent cancer in people who carry genetic variants that increase the risk of certain cancers. Scientists are also doing studies to find additional genetic changes that can increase a person’s risk of cancer. There is also much work being done to increase the accuracy and consistency of classifying the genetic variants detected by testing.

The goal of another avenue of research is to provide doctors and patients with better information about the cancer risks associated with specific genetic variants, particularly variants of uncertain significance. For example, one research approach, called saturation genome editing, used CRISPR-Cas9 gene editing to create 4000 different genetic variants throughout a region of the BRCA1 gene that is important for its function as a tumor suppressor. The gene editing was done in special cells that cannot survive without a functioning BRCA1 protein. For variants where clinical data were available, the gene editing results agreed with clinical findings more than 96% of the time, suggesting that this approach can be used to classify the cancer risks associated with variants of uncertain significance in other genes.

Collaborative efforts that bring together genomic and clinical data, such as the BRCA Exchange web portal, are providing a comprehensive resource that people can refer to when they get the results of a genetic test and want to know the clinical significance of particular gene variant. ClinVar is a public archive to support the accumulation of evidence for the clinical significance of genetic variants. 

NCI runs an active program of genome-wide association studies (GWAS) through its Cancer Genomics Research Laboratory. This technique compares the genomes from many different people to find genetic markers associated with particular observable characteristics or risk of disease. The goal is to understand how genes contribute to the disease and to use that understanding to help develop better prevention and treatment strategies. 

Additional NCI research is focused on improving genetic counseling methods and outcomes, studying the risks and benefits of at-home genetic testing, and evaluating the effects of advertising of these tests on patients, providers, and the health care system. Researchers are also working to improve the laboratory methods available for genetic testing.

Selected References
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