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.
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.
DNA (usually from a blood or saliva sample) is needed for all of these tests. The sample is sent to a laboratory for analysis. It usually takes about a month to get the test results.
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.
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 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 BRCA2mutations, scientists will learn more about these changes and cancer risk. Genetic counseling can help a person understand what an ambiguous change in BRCA1 or BRCA2may 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.
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).Contact your Doctor if you have questions or concerns about BRCA Genetic Testing.