BRCA Mutations: Cancer Risk and Genetic Testing
What are BRCA1 and BRCA2?
BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of each cell’s genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.
Specific inherited mutations in BRCA1 and BRCA2 most notably increase the risk of female breast and ovarian cancers, but they have also been associated with increased risks of several additional types of cancer. People who have inherited mutations in BRCA1 and BRCA2 tend to develop breast and ovarian cancers at younger ages than people who do not have these mutations.
A harmful BRCA1 or BRCA2 mutation can be inherited from a person’s mother or father. Each child of a parent who carries a mutation in one of these genes has a 50% chance (or 1 chance in 2) of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a person’s second copy of the gene is normal.
How much does having a BRCA1 or BRCA2 gene mutation increase a woman’s risk of breast and ovarian cancer?
A woman’s lifetime risk of developing breast and/or ovarian cancer is greatly increased if she inherits a harmful mutation in BRCA1 or BRCA2.
Breast cancer: About 12% of women in the general population will develop breast cancer sometime during their lives (1). By contrast, a recent large study estimated that about 72% of women who inherit a harmful BRCA1 mutation and about 69% of women who inherit a harmful BRCA2 mutation will develop breast cancer by the age of 80 (2).
Like women from the general population, those with harmful BRCA1 or BRCA2 mutations also have a high risk of developing a new primary cancer in the opposite (contralateral) breast in the years following a breast cancer diagnosis. It has been estimated that, by 20 years after a first breast cancer diagnosis, about 40% of women who inherit a harmful BRCA1 mutation and about 26% of women who inherit a harmful BRCA2 mutation will develop cancer in their other breast (2).
Ovarian cancer: About 1.3% of women in the general population will develop ovarian cancer sometime during their lives (1). By contrast, it is estimated that about 44% of women who inherit a harmful BRCA1 mutation and about 17% of women who inherit a harmful BRCA2 mutation will develop ovarian cancer by the age of 80 (2).
What other cancers have been linked to mutations in BRCA1 and BRCA2?
Harmful mutations in BRCA1 and BRCA2 increase the risk of several cancers in addition to breast and ovarian cancer. These include fallopian tube cancer (3, 4) and peritoneal cancer (5). Men with BRCA2 mutations, and to a lesser extent BRCA1 mutations, are also at increased risk of breast cancer (6) and prostate cancer (7). Both men and women with harmful BRCA1 or BRCA2 mutations are at increased risk of pancreatic cancer (8, 9).
Certain mutations in BRCA2 (also known as FANCD1), if they are inherited from both parents, can cause a rare form of Fanconi anemia (subtype FA-D1), a syndrome that is associated with childhood solid tumors and development of acute myeloid leukemia (10, 11). Likewise, certain mutations in BRCA1 (also known as FANCS), if they are inherited from both parents, can cause another Fanconi anemia subtype (12).
Are mutations in BRCA1 and BRCA2 more common in certain racial/ethnic populations than others?
Yes. For example, people of Ashkenazi Jewish descent have a higher prevalence of harmful BRCA1 and BRCA2 mutations than people in the general U.S. population. Other ethnic and geographic populations around the world, such as the Norwegian, Dutch, and Icelandic peoples, also have a higher prevalence of specific harmful BRCA1 and BRCA2 mutations.
In addition, the prevalence of specific harmful BRCA1 and BRCA2 mutations may vary among individual racial and ethnic groups in the United States, including African Americans, Hispanics, Asian Americans, and non-Hispanic whites (13, 14).
This question is under intensive study, since identifying population-specific mutations in these genes can greatly simplify the genetic testing for BRCA1 and BRCA2 mutations.
Are genetic tests available to detect BRCA1 and BRCA2 mutations?
Yes, several different tests are available. Some tests look for a specific harmful BRCA1 or BRCA2 gene mutation that has already been identified in another family member. Other tests check for all of the known harmful mutations in both genes. Multigene (panel) testing uses next-generation sequencing to look for harmful mutations in many genes that are associated with an increased risk of breast and ovarian cancer, including BRCA1 and BRCA2, at the same time.
Who should consider genetic testing for BRCA1 and BRCA2 mutations?
Because harmful BRCA1 and BRCA2 gene mutations are relatively rare in the general population, most experts agree that mutation testing of individuals who do not have cancer should be performed only when the person’s individual or family history suggests the possible presence of a harmful mutation in BRCA1 or BRCA2.
The United States Preventive Services Task Force recommends that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a family history that is associated with an increased risk of a harmful mutation in one of these genes (15).
Several screening tools are available to help health care providers with this evaluation (15). These tools assess personal or family history factors that are associated with an increased likelihood of having a harmful mutation in BRCA1 or BRCA2, such as:
- Breast cancer diagnosed before age 50 years
- Cancer in both breasts in the same woman
- Both breast and ovarian cancers in either the same woman or the same family
- Multiple breast cancers in the family
- Two or more primary types of BRCA1- or BRCA2-related cancers in a single family member
- Cases of male breast cancer
- Ashkenazi Jewish ethnicity
When an individual has a family history that is suggestive of the presence of a BRCA1 or BRCA2 mutation, it may be most informative to first test a family member who has cancer, if that person is still alive and willing to be tested. If that person has a harmful BRCA1 or BRCA2 mutation, then other family members may want to consider genetic counseling to learn more about their potential risks and whether genetic testing for mutations in BRCA1 and BRCA2 might be appropriate for them.
If it can’t be determined whether the family member with cancer has a harmful BRCA1 or BRCA2 mutation, members of a family whose history is suggestive of the presence of a BRCA1 or BRCA2 gene mutation may still want to consider genetic counseling for possible testing.
Some individuals—for example, those who were adopted at birth—may not know their family history. If a woman with an unknown family history has an early-onset breast cancer or ovarian cancer or a man with an unknown family history is diagnosed with breast cancer, that individual may want to consider genetic counseling and testing for a BRCA1 or BRCA2 mutation.
Professional societies do not recommend that children under age 18, even those with a family history suggestive of a harmful BRCA1 or BRCA2 mutation, undergo genetic testing for BRCA1 or BRCA2 This is because there are no risk-reduction strategies that are specifically meant for children, and children's risks of developing a cancer type associated with a BRCA1 or BRCA2 mutation are extremely low.
Should people considering genetic testing for BRCA1 and BRCA2 mutations talk with a genetic counselor?
Genetic counseling is generally recommended before and after any genetic test for an inherited cancer syndrome. This counseling should be performed by a 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
- The medical implications of a positive or a negative test result
- The possibility that a test result might not be informative (that is, it might find an alteration whose effect on cancer risk is not known)
- The psychological risks and benefits of genetic test results
- The risk of passing a mutation to children
- Explanation of the specific test(s) that might be used and the technical accuracy of the test(s)
Does health insurance cover the cost of BRCA1 and BRCA2 mutation testing?
People considering BRCA1 and BRCA2 mutation testing may want to confirm their insurance coverage for genetic counseling and testing.
The Affordable Care Act considers genetic counseling and BRCA1 and BRCA2 mutation testing a covered preventive service for women who have not already been diagnosed with a cancer related to a mutation in BRCA1 or BRCA2 and who meet the United States Preventive Services Task Force recommendations for testing.
Medicare covers BRCA1 and BRCA2 mutation testing for women who have signs and symptoms of breast, ovarian, or other cancers that are related to mutations in BRCA1 and BRCA2 but not for unaffected women.
Some of the genetic testing companies that offer testing for BRCA1 and BRCA2 mutations may offer testing at no charge to patients who lack insurance and meet specific financial and medical criteria.
What do BRCA1 or BRCA2 genetic test results mean?
BRCA1 and BRCA2 gene mutation testing can give several possible results: a positive result, a negative result, or an ambiguous or uncertain result.
Positive result. A positive test result indicates that a person has inherited a known harmful mutation in BRCA1 or BRCA2 and, therefore, has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when an individual will actually develop cancer. Some women who inherit a harmful BRCA1 or BRCA2 mutation never develop breast or ovarian cancer.
A positive test result may also have important implications for family members, including future generations.
- Both men and women who inherit a harmful BRCA1 or BRCA2 mutation, whether or not they develop cancer themselves, may pass the mutation on to their sons and daughters. Each child has a 50% chance of inheriting a parent’s mutation.
- If a person learns that he or she has inherited a harmful BRCA1 or BRCA2 mutation, this will mean that each of his or her full siblings has a 50% chance of having inherited the mutation as well.
Negative result. A negative test result can be more difficult to understand than a positive result because what the result means depends in part on an individual’s family history of cancer and whether a BRCA1 or BRCA2 mutation has been identified in a blood relative.
If a close (first- or second-degree) relative of the tested person is known to carry a harmful BRCA1 or BRCA2 mutation, a negative test result is clear: it means that person does not carry the harmful mutation that is responsible for their family’s cancer risk, and thus cannot pass it on to their children. Such a test result is called a true negative. A person with such a test result is currently thought to have the same risk of cancer as someone in the general population.
If the tested person has a family history that suggests the possibility of having a harmful mutation in BRCA1 or BRCA2 but complete gene testing identifies no such mutation in the family, a negative result is less clear. The likelihood that genetic testing will miss a known harmful BRCA1 or BRCA2 mutation is very low, but it could happen. Moreover, scientists continue to discover new BRCA1 and BRCA2 mutations and have not yet identified all potentially harmful ones. Therefore, it is possible that a person in this scenario with a "negative" test result may actually have a harmful BRCA1 or BRCA2 mutation that has not previously been identified.
It is also possible for people to have a mutation in a gene other than BRCA1 or BRCA2 that increases their cancer risk but is not detectable by the test used. It is important that people considering genetic testing for BRCA1 and BRCA2 mutations discuss these potential uncertainties with a genetic counselor before undergoing testing.
Ambiguous or uncertain result. Sometimes, a genetic test finds a change in BRCA1 or BRCA2 that has not been previously associated with cancer. This type of test result may be described as “ambiguous” (often referred to as “a genetic variant of uncertain significance”) because it isn’t known whether this specific genetic change is harmful. One study found that 10% of women who underwent BRCA1 and BRCA2 mutation testing had this type of ambiguous result (16).
As more research is conducted and more people are tested for BRCA1 and BRCA2 mutations, scientists will learn more about these changes and cancer risk. Genetic counseling can help a person understand what an ambiguous change in BRCA1 or BRCA2 may mean in terms of cancer risk. Over time, additional studies of variants of uncertain significance may result in a specific mutation being reclassified as either clearly harmful or clearly not harmful.
How can a person who has a harmful BRCA1 or BRCA2 gene mutation manage their risk of cancer?
Several options are available for managing cancer risk in individuals who have a known harmful BRCA1 or BRCA2 mutation. These include enhanced screening, prophylactic (risk-reducing)
Enhanced Screening. Some women who test positive for BRCA1 and BRCA2 mutations may choose to start breast cancer screening at younger ages, and/or have more frequent
Enhanced screening may increase the chance of detecting breast cancer at an early stage, when it may have a better chance of being treated successfully. Studies have shown that MRI may be better able than mammography to find tumors, particularly in younger women at high risk of breast cancer (18, 19). However, mammography can also identify some breast cancers that are not identified by MRI (20). Also, MRI may be less specific (that is, lead to more false-positive results) than mammography.
Several organizations, such as the American Cancer Society and the National Comprehensive Cancer Network, now recommend annual screening with both mammography and MRI for women who have a high risk of breast cancer. Women who test positive for a BRCA1 or BRCA2 mutation should ask their
No effective ovarian cancer screening methods currently exist. Some groups recommend transvaginal ultrasound, blood tests for the antigen CA-125, and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 mutations, but none of these methods appears to detect ovarian tumors at an early enough stage to reduce the risk of dying from ovarian cancer (21). For a screening method to be considered effective, it must have demonstrated reduced mortality from the disease of interest. This standard has not yet been met for ovarian cancer screening.
The benefits of screening for breast and other cancers in men who carry harmful mutations in BRCA1 or BRCA2 are also not known, but some expert groups recommend that men who are known to carry a harmful mutation undergo regular breast exams as well as testing for prostate cancer.
Prophylactic (Risk-reducing) Surgery. Prophylactic surgery involves removing as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed (bilateral prophylactic mastectomy) to reduce their risk of breast cancer. Surgery to remove a woman's ovaries and fallopian tubes (bilateral prophylactic salpingo-oophorectomy) can help reduce her risk of ovarian cancer. (Ovarian cancers often originate in the fallopian tubes, so it is essential that they
Whether bilateral prophylactic mastectomy reduces breast cancer risk in men with a harmful BRCA1 or BRCA2 mutation or a family history of breast cancer isn’t known. Therefore, bilateral prophylactic mastectomy for men at high risk of breast cancer is considered an experimental procedure, and insurance companies will not normally cover it.
Prophylactic surgery does not guarantee that cancer will not develop because not all at-risk tissue can be removed by these procedures. That is why these surgical procedures are often described as “risk-reducing” rather than “preventive.” Some women have developed breast cancer, ovarian cancer, or primary peritoneal carcinomatosis (a type of cancer similar to ovarian cancer) even after risk-reducing surgery. Nevertheless, these surgical procedures confer substantial benefits. For example, research demonstrates that women who underwent bilateral prophylactic salpingo-oophorectomy had a nearly 80% reduction in risk of dying from ovarian cancer, a 56% reduction in risk of dying from breast cancer (22), and a 77% reduction in risk of dying from any cause during the studies’ follow-up periods (23).
The reduction in breast and ovarian cancer risk from
Chemoprevention. Chemoprevention is the use of medicines to try to reduce the risk of cancer. Although two chemopreventive drugs (tamoxifen and raloxifene) have been approved by the U.S. Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at increased risk, the role of these drugs in women with harmful BRCA1 or BRCA2 mutations is not yet clear. However, these medications may be an option for women who don’t choose, or can’t undergo, surgery.
Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in women who carry harmful mutations in BRCA2 (24), as well as the risk of cancer in the opposite breast among BRCA1 and BRCA2 mutation carriers previously diagnosed with breast cancer (25, 26). Studies have not examined the effectiveness of raloxifene in BRCA1 and BRCA2 mutation carriers specifically.
What are some of the benefits of genetic testing for breast and ovarian cancer risk?
There can be benefits to genetic testing, regardless of whether a person receives a positive or a negative result.
The potential benefits of a true negative result include a sense of relief regarding the future risk of cancer, learning that one's children are not at risk of inheriting the family's cancer susceptibility, and the possibility that special checkups, tests, or preventive surgeries may not be needed.
A positive test result may bring relief by resolving uncertainty regarding future cancer risk and may allow people to make informed decisions about their future health care, including taking steps to reduce their cancer risk. In addition, people who have a positive test result may choose to participate in medical research that could, in the long run, help reduce deaths from hereditary breast and ovarian cancer.
What are some of the possible harms of genetic testing for BRCA gene mutations?
The direct medical harms of genetic testing are minimal, but knowledge of test results may have harmful effects on a person’s emotions, social relationships, finances, and medical choices.
People who receive a positive test result may feel anxious, depressed, or angry, particularly immediately after they learn the result. People who learn that they carry a BRCA mutation may have difficulty making choices about whether to have preventive surgery or about which surgery to have.
People who receive a negative test result may experience “survivor guilt,” caused by the knowledge that they likely do not have an increased risk of developing a disease that affects one or more loved ones.
Because genetic testing can reveal information about more than one family member, the emotions caused by test results can create tension within families. Test results can also affect personal life choices, such as decisions about career, marriage, and childbearing.
Violations of privacy and of the confidentiality of genetic test results are additional potential risks. However, the federal Health Insurance Portability and Accountability Act and various state laws protect the privacy of a person’s genetic information. Moreover, the federal Genetic Information Nondiscrimination Act, along with many state laws, prohibits discrimination based on genetic information in relation to health insurance and employment, although it does not cover life insurance, disability insurance, or long-term care insurance.
Finally, there is a small chance that test results may not be accurate, leading people to make medical decisions based on incorrect information. Although it is rare that results are inaccurate, people with these concerns should address them during genetic counseling.
What are the implications of having a harmful BRCA1 or BRCA2 mutation for breast and ovarian cancer prognosis and treatment?
Some studies have investigated whether there are clinical differences between breast and ovarian cancers that are associated with harmful BRCA1 or BRCA2 mutations and cancers that are not associated with these mutations.
- There is evidence that, over the long term, women who carry these mutations are more likely to develop
a secondcancer in either the same (28) (ipsilateral) breast or the opposite (2) (contralateral) breast than women who do not carry these mutations. Thus, some women with a harmful BRCA1 or BRCA2 mutation who develop breast cancer in one breast opt for a bilateral mastectomy, even if they would otherwise be candidates for breast-conserving surgery. Because of the increased risk of a second breast cancer among BRCA1 and BRCA2 mutation carriers, some doctors recommend that women with early-onset breast cancer and those whose family history is consistent with a mutation in one of these genes have genetic testing when breast cancer is diagnosed.
- Breast cancers in women with a harmful BRCA1 mutation tend to be "triple-negative cancers" (that is, the breast cancer cells do not have estrogen receptors, progesterone receptors, or large amounts of HER2/neu protein), which generally have
poorerprognosis than other breast cancers.
- Because the BRCA1 and BRCA2 genes are involved in DNA repair, some investigators have suggested that cancer cells with a harmful mutation in either of these genes may be more sensitive to anticancer agents that act by damaging DNA, such as cisplatin. A class of drugs called PARP inhibitors, which block the repair of DNA damage, have been found to arrest the growth of cancer cells that have BRCA1 or BRCA2 mutations. Several PARP inhibitors, including olaparib (Lynparza™) and
rucaparib, have been approved by the U.S. Food and Drug Administration for the treatment of advanced ovarian cancers in women with a BRCA1 or BRCA2 mutation. Olaparib is also approved for the treatment of HER2-negative metastatic breast cancers in women with a BRCA1 or BRCA2 mutation.
Do inherited mutations in other genes increase the risk of breast and/or ovarian tumors?
Yes. Although harmful mutations in BRCA1 and BRCA2 are responsible for the disease in nearly half of families with multiple cases of breast cancer and up to 90% of families with both breast and ovarian cancer, mutations in a number of other genes have been associated with increased risks of breast and/or ovarian cancers (29, 30). These other genes include several that are associated with the inherited disorders Cowden syndrome, Peutz-Jeghers syndrome, Li-Fraumeni syndrome, and Fanconi anemia, which increase the risk of many cancer types.
Most mutations in these other genes do not increase breast cancer risk to the same extent as mutations in BRCA1 and BRCA2. However, researchers have reported that inherited mutations in the PALB2 gene are associated with a risk of breast cancer nearly as high as that associated with inherited BRCA1 and BRCA2 mutations (31). They estimated that 33% of women who inherit a harmful mutation in PALB2 will develop breast cancer by age 70 years.
Recently, mutations in other genes that increase breast and ovarian cancer risk have been identified. These include mutations in the genes TP53, CDH1, and CHEK2, which increase the risk of breast cancer, and in RAD51C, RAD51D, and STK11, which increase the risk of ovarian cancer (32). Genetic testing for these other mutations is available as part of multigene (panel) testing. However, expert groups have not yet developed specific guidelines for who should be tested, or for the management of breast or ovarian cancer risk in people with these other high-risk mutations.