BRCA Gene Mutations: Cancer Risk and Genetic Testing
What are BRCA1 and BRCA2?
BRCA1 (BReast CAncer gene 1) and BRCA2 (BReast CAncer gene 2) are genes that produce proteins that help repair damaged DNA. Everyone has two copies of each of these genes—one copy inherited from each parent. BRCA1 and BRCA2 are sometimes called tumor suppressor genes because when they have certain changes, called harmful (or pathogenic) variants (or mutations), cancer can develop.
People who inherit harmful variants in one of these genes have increased risks of several cancers—most notably breast and ovarian cancer, but also several additional types of cancer. People who have inherited a harmful variant in BRCA1 and BRCA2 also tend to develop cancer at younger ages than people who do not have such a variant.
A harmful variant in BRCA1 or BRCA2 can be inherited from either parent. Each child of a parent who carries any mutation in one of these genes has a 50% chance (or 1 in 2 chance) of inheriting the mutation. Inherited mutations—also called germline mutations or variants—are present from birth in all cells in the body.
Even if someone has inherited a harmful variant in BRCA1 or BRCA2 from one parent, they would have inherited a normal copy of that gene from the other parent (that’s because in most cases, embryos with a harmful variant from each parent cannot develop). But the normal copy can be lost or change in some cells in the body during that person’s lifetime. Such a change is called a somatic alteration. Cells that don’t have any functioning BRCA1 or BRCA2 proteins can grow out of control and become cancer.
How much does an inherited harmful variant in BRCA1 or BRCA2 increase a woman’s risk of breast and ovarian cancer?
A woman’s lifetime risk of developing breast and/or ovarian cancer is markedly increased if she inherits a harmful variant in BRCA1 or BRCA2, but the degree of increase varies depending on the mutation.
Breast cancer: About 13% of women in the general population will develop breast cancer sometime during their lives (1). By contrast, 55%–72% of women who inherit a harmful BRCA1 variant and 45%–69% of women who inherit a harmful BRCA2 variant will develop breast cancer by 70–80 years of age (2–4). The risk for any one woman depends on a number of factors, some of which have not been fully characterized.
Like women with breast cancer in general, those with harmful BRCA1 or BRCA2 variants also have an increased risk of developing cancer in the opposite (contralateral) breast in the years following a breast cancer diagnosis (2). The risk of contralateral breast cancer increases with the time since a first breast cancer, reaching 20%–30% at 10 years of follow-up and 40%–50% at 20 years, depending on the gene involved.
Ovarian cancer: About 1.2% of women in the general population will develop ovarian cancer sometime during their lives (1). By contrast, 39%–44% of women who inherit a harmful BRCA1 variant and 11%–17% of women who inherit a harmful BRCA2 variant will develop ovarian cancer by 70–80 years of age (2–4).
What other cancers are linked to harmful variants in BRCA1 and BRCA2?
Harmful variants in BRCA1 and BRCA2 increase the risk of several additional cancers. In women, these include fallopian tube cancer (5, 6) and primary peritoneal cancer (7), both of which start in the same cells as the most common type of ovarian cancer. Men with BRCA2 variants, and to a lesser extent BRCA1 variants, are also at increased risk of breast cancer (8) and prostate cancer (9–11). Both men and women with harmful BRCA1 or BRCA2 variants are at increased risk of pancreatic cancer, although the risk increase is low (12–14).
In addition, certain variants in BRCA1 and BRCA2 can cause subtypes of Fanconi anemia, a rare syndrome that is associated with childhood solid tumors and development of acute myeloid leukemia (15–17). The mutations that cause these Fanconi anemia subtypes have a milder effect on protein function than the mutations that cause breast and ovarian cancer. Children who inherit one of these variants from each parent will develop Fanconi anemia.
Are harmful variants in BRCA1 and BRCA2 more common in certain racial/ethnic populations than others?
Yes. The likelihood of carrying an inherited mutation in BRCA1 or BRCA2 (the prevalence) varies across specific population groups. While the prevalence in the general population is about 0.2%–0.3% (or about 1 in 400), about 2.0% of people of Ashkenazi Jewish descent carry a harmful variant in one of these two genes and the variants are usually one of three specific variants, called founder mutations. Other populations, such as Norwegian, Dutch, and Icelandic peoples, also have founder mutations (18).
Different racial/ethnic and geographic populations also tend to carry different variants in these genes. For instance, African Americans have BRCA1 variants that are not seen in other racial/ethnic groups in the United States (19–21). Most people of Ashkenazi Jewish descent in the United States who carry a BRCA variant have one of three specific variants (two in BRCA1 and one in BRCA2). In the Icelandic population, a different variant in BRCA1 is common among those who inherit a mutation in BRCA1.
Who should consider genetic counseling and testing for BRCA1 and BRCA2 variants?
Anyone who is concerned about the possibility that they may have a harmful variant in the BRCA1 or BRCA2 gene should discuss their concerns with their health care provider or a genetic counselor.
Tests are available to see if someone has inherited a harmful variant in BRCA1 and BRCA2. However, testing is not currently recommended for the general public. Instead, expert groups recommend that testing be focused on those who have a higher likelihood of carrying a harmful BRCA1 or BRCA2 variant, such as those who have a family history of certain cancers. Testing can be appropriate for both people without cancer as well as people who have been diagnosed with cancer. If someone knows they have a mutation in one of these genes, they can take steps to reduce their risk or detect cancer early. And if they have cancer, the information about their mutation may be important for selecting treatment.
Before testing is done, a person will usually have a risk assessment, in which they meet with a genetic counselor or other health care provider to review factors such as which of their relatives had cancer, what cancers they had, and at what ages they were diagnosed. If this assessment suggests that someone has an increased risk of carrying a harmful BRCA1 or BRCA2 gene variant, their genetic counselor can discuss the benefits and harms of testing with them and order the appropriate genetic test, if the individual decides to have genetic testing (22).
Some people may choose to have genetic testing via direct-to-consumer (DTC) testing. Genetic counseling is recommended for those people as well to help them understand the test results and to make sure the most appropriate test was done. People should be aware that DTC tests may not be comprehensive, in that some tests do not test for all of the harmful mutations in the two genes. So receiving a negative result with a DTC test may not mean that they don’t have a harmful variant in BRCA1 or BRCA2.
The United States Preventive Services Task Force recommends risk assessment for women who have a personal or family history of breast, ovarian, fallopian tube, or peritoneal cancer or whose ancestry is associated with having harmful BRCA1 and BRCA2 variants, as well as follow-up genetic counseling as appropriate.
The National Comprehensive Cancer Network (NCCN) has criteria for genetic testing of BRCA1 and BRCA2 as well as for several other genes (including CDH1, PALB2, PTEN, and TP53) that are associated with increased risk of breast and/or ovarian cancer (23). NCCN recommends risk assessment for people who have a blood relative with a known or likely harmful variant in any of these genes; who have certain personal and/or family histories of cancer (cancer diagnosed at a younger age, certain types of cancer, people with two or more cancer diagnoses, or families with multiple cases of cancer); or who have certain inherited cancer predisposition disorders, such as Cowden syndrome, Peutz-Jeghers syndrome, Li-Fraumeni syndrome, or Fanconi anemia.
The American Society of Clinical Oncology recommends that all women diagnosed with epithelial ovarian cancer be offered genetic testing for inherited variants in BRCA1, BRCA2, and other ovarian cancer susceptibility genes, regardless of the clinical features of their disease or their family history (24).
Professional societies do not recommend that children under age 18 undergo genetic testing for BRCA1 and BRCA2 variants. This is because there are no risk-reduction strategies that are specifically meant for children, and children are very unlikely to develop a cancer related to an inherited BRCA variant.
Testing for inherited BRCA1 and BRCA2 variants may be done using a blood sample or a saliva sample. That is because blood cells and cells that are present in saliva, like every cell in the body, contain the BRCA1 and BRCA2 genes. Sometimes people with cancer find out that they have a BRCA1 or BRCA2 mutation when their tumor is tested to see if they are a candidate for treatment with a particular targeted therapy. Because harmful BRCA variants reported in the tumor may be of somatic or germline origin, someone with such a variant in their tumor should consider having a germline genetic (blood) test to determine if the variant was inherited.
When a family history suggests the possibility that someone without cancer may have inherited a harmful variant in BRCA1 or BRCA2, it is best for a family member who has already been diagnosed with cancer to be tested, if such a person is alive and willing to get tested. If such testing reveals a known harmful variant, then testing the individual for that variant will provide a clear indication of whether they also carry it. If all family members with cancer are deceased or are unwilling or unable to have genetic testing, testing family members who have not been diagnosed with cancer may still be of value and provide good information.
Does health insurance cover the cost of genetic testing for BRCA1 and BRCA2 variants?
People considering BRCA1 and BRCA2 variant testing may want to confirm their insurance coverage for genetic counseling and testing. Genetic counselors can often help answer questions about insurance coverage for genetic testing.
Some genetic testing companies may offer testing for inherited BRCA1 and BRCA2 variants at no charge to patients who lack insurance and meet specific financial and medical criteria.
What do BRCA1 and BRCA2 genetic test results mean?
BRCA1 and BRCA2 mutation testing can give several possible results: a positive result, a negative result, or a variant of uncertain significance (VUS) result.
Positive result. A positive test result indicates that a person has inherited a known harmful variant in BRCA1 or BRCA2 (these are typically called “pathogenic” or “likely pathogenic” variants on laboratory test reports) and has an increased risk of developing certain cancers. However, a positive test result cannot tell whether or when the tested individual will develop cancer. Some people who inherit a harmful BRCA1 or BRCA2 variant never develop 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 variant, whether or not they develop cancer themselves, may pass the variant to their children. Each child has a 50% chance of inheriting a parent’s variant.
- All blood relatives of a person who has inherited a harmful BRCA1 or BRCA2 variant are at some increased risk of having the variant themselves. For example, each of that person’s full siblings has a 50% chance of having inherited the variant as well.
- Very rarely, an individual may test positive for a harmful variant not inherited from either parent. This is called a de novo (or “new”) variant. Such a variant is one that arose in a germ cell (sperm or egg) of one of the parents and is present in all the cells of the person who grew from that cell. The children of someone with a de novo variant (but not his or her siblings) are at risk of inheriting the variant.
Negative result. A negative test result can have several meanings, depending on the personal and family medical history of the person who is tested and whether or not a harmful mutation has already been identified in the family. If a close blood relative of the tested person is known to carry a harmful BRCA1 or BRCA2 variant, a negative test result is clear: it means the tested person did not inherit the harmful variant that is present in the family and cannot pass it to their children. A person with such a test result, called a true negative, has a risk of cancer that is similar to that of someone in the general population. However, there are other factors besides genetic factors that may increase the risk of cancer, such as radiation exposures at an early age, and those factors should be considered in assessing their risk of cancer.
If the tested person has no personal history of cancer and their family isn’t known to carry a harmful variant, then in this case, a negative test result is considered to be “uninformative.” There are several possible reasons why someone could have an uninformative negative test result:
- Without testing family members who have had cancer, it is uncertain whether the negative test means that the person did not inherit a BRCA1 or BRCA2 mutation that is present in the family or whether the family history might be due to a mutation in another gene that was not tested or to other, nongenetic risk factors.
- The individual may have a harmful variant that is not detectable by current testing technologies.
- Rarely, there could be an error in the testing, either because inappropriate tests were recommended or ordered, genetic variants were interpreted incorrectly, or the wrong results were relayed to patients (25).
Variant of Uncertain Significance (VUS) result. Sometimes, a genetic test finds a change in BRCA1 or BRCA2 that has not been previously associated with cancer and is uncommon in the general population. This type of test result is called “a variant of uncertain significance,” or VUS, because it isn’t known whether this specific genetic change is harmful.
As more research is conducted and more people are tested for BRCA1 and BRCA2 variants, scientists will learn more about uncertain changes and cancer risk. Clinicians and scientists are actively working to share information on these mutations so that they can be reclassified as either clearly harmful or clearly not harmful (26, 27).
Genetic counseling can help a person understand what a VUS in BRCA1 or BRCA2 may mean in terms of their cancer risk. Until the interpretation of the variant is clarified, management of risk should be based on family history and other risk factors. However, it is important that a person who has a VUS test result regularly obtains updated information from the testing provider in case that VUS is reclassified as a harmful or likely harmful variant. Testing providers have different policies about notifying a tested person of a change in the interpretation of a VUS test result. Some will contact the tested person directly, whereas others place the responsibility on the tested person to check back in on a regular basis to learn of updates to the interpretation of their VUS test result.
How can a person who has inherited a harmful BRCA1 or BRCA2 gene variant reduce their risk of cancer?
Several options are available for reducing cancer risk in individuals who have inherited a harmful BRCA1 or BRCA2 variant. These include enhanced screening, risk-reducing surgery (sometimes referred to as prophylactic surgery), and chemoprevention.
Enhanced screening. Some women who test positive for harmful BRCA1 and BRCA2 variants may choose to start breast cancer screening at younger ages, have more frequent screening than is recommended for women with an average risk of breast cancer, or have screening with magnetic resonance imaging (MRI) in addition to mammography.
No effective ovarian cancer screening methods are known. Some groups recommend transvaginal ultrasound, blood tests for the CA-125 antigen (which can be present at higher-than-normal levels in women with ovarian cancer), and clinical examinations for ovarian cancer screening in women with harmful BRCA1 or BRCA2 variants. However, none of these methods appear to detect ovarian tumors at an early enough stage to improve long-term survival (28).
The benefits of screening men who carry harmful variants in BRCA1 or BRCA2 for breast and other cancers are not known. Some expert groups recommend that such men undergo regular annual clinical breast exams starting at age 35 (23). The National Comprehensive Cancer Network (NCCN) guidelines recommend that men with harmful germline variants in BRCA1 or BRCA2 consider having a discussion with their doctor about prostate-specific antigen (PSA) testing for prostate cancer screening starting at age 40 (29).
Some experts recommend the use of ultrasound or MRI/magnetic retrograde cholangiopancreatography to screen for pancreatic cancer in people who are known to carry a harmful BRCA1 or BRCA2 variant and who have a close blood relative with pancreatic cancer (30). However, it is not yet clear whether pancreatic cancer screening and early pancreatic cancer detection reduces the overall risk of dying from a pancreatic cancer.
All of these screening approaches have potential harms as well as possible benefits. For example, MRI is more likely than mammography to result in false-positive findings. And there is some concern that women who have a harmful BRCA variant might be particularly sensitive to the DNA-damaging effects of tests that involve radiation (such as mammography) because they already have a defect in DNA repair (31).
Risk-reducing surgery. Risk-reducing, or prophylactic, surgery involves removing as much of the "at-risk" tissue as possible. Women may choose to have both breasts removed (bilateral risk-reducing mastectomy) to reduce their risk of breast cancer. Surgery to remove a woman's ovaries and fallopian tubes (bilateral risk-reducing salpingo-oophorectomy) can help reduce her risk of ovarian cancer. (Ovarian cancers often originate in the fallopian tubes, so it is essential that they be removed along with the ovaries.) Removing the ovaries may also reduce the risk of breast cancer in premenopausal women by eliminating a source of hormones that can fuel the growth of some types of breast cancer.
These surgeries are irreversible, and each has potential complications or harms. These include bleeding or infection, anxiety and concerns about body image (bilateral risk-reducing mastectomy), and early menopause in premenopausal women (bilateral risk-reducing salpingo-oophorectomy).
Risk-reducing 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 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 greatly reduce risk. For example, in several studies women who underwent bilateral salpingo-oophorectomy had a nearly 80% reduction in risk of dying from ovarian cancer, a 56% reduction in risk of dying from breast cancer (32), and a 77% reduction in risk of dying from any cause during the studies’ follow-up periods (33).
The reduction in breast and ovarian cancer risk from removal of the ovaries and fallopian tubes appears to be similar for carriers of BRCA1 and BRCA2 variants (33).
Chemoprevention. Chemoprevention is the use of medicines to reduce the risk of cancer. Two chemopreventive drugs (tamoxifen [Nolvadex] and raloxifene [Evista]) have been approved by the Food and Drug Administration (FDA) to reduce the risk of breast cancer in women at increased risk, but the role of these drugs in women with harmful BRCA1 or BRCA2 variants is not yet clear. Data from three studies suggest that tamoxifen may be able to help lower the risk of breast cancer in women who carry harmful variants in BRCA2 (34) and of cancer in the opposite breast among BRCA1 and BRCA2 variant carriers previously diagnosed with breast cancer (35, 36). Studies have not examined the effectiveness of raloxifene in BRCA1 and BRCA2 variant carriers specifically.
However, these medications may be an option for women who choose not to, or who cannot, undergo surgery. The potential harms of these drugs include menopausal symptoms, blood clots, stroke, increased risk of endometrial cancer (tamoxifen), and allergic reactions (raloxifene).
Both women in the general population, as well as those with harmful BRCA1 or BRCA2 variants, who have ever used oral contraceptives (birth control pills) have about a 50% lower risk of ovarian cancer than women who have never used oral contraceptives (37). Potential harms of oral contraceptives include increased risk of breast cancer, increased risk that a human papillomavirus (HPV) infection will become cervical cancer, and possible cardiovascular effects among older reproductive-age women.
What are the benefits of genetic testing for BRCA1 and BRCA2 variants?
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 check-ups, tests, or risk-reducing surgeries may not be needed.
A positive test result may allow people to make informed decisions about their future health care, including taking steps to reduce their cancer risk.
What are the possible harms of genetic testing for BRCA1 and BRCA2 variants?
The direct medical harms of genetic testing are minimal, but knowledge of test results, whether positive or negative, may have harmful effects on a person’s emotions, social relationships, finances, and medical choices.
Dealing with uncertainty of an uninformative negative or a VUS test result is another potential harm. For this reason, it is important to have genetic counseling before undergoing genetic testing.
Results of genetic tests 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.
What are the treatment implications of having a harmful BRCA1 or BRCA2 variant for patients who have already developed cancer?
Because the BRCA1 and BRCA2 genes are involved in DNA repair, tumors with alterations in either gene are particularly sensitive to anticancer agents that act by damaging DNA, such as cisplatin (38).
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 harmful BRCA1 or BRCA2 variants. Four PARP inhibitors—olaparib [Lynparza], rucaparib [Rubraca], niraparib [Zejula], and talazoparib [Talzenna]—are approved by the FDA to treat certain cancers bearing harmful variants in BRCA1 or BRCA2. (In some cases, these are used whether or not a BRCA1 or BRCA2 mutation is present.)
Breast cancers with harmful BRCA1 variants are more likely 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) than sporadic breast cancers or breast cancers with harmful BRCA2 variants. Triple-negative cancers are harder to treat and have a poorer prognosis than other types of breast cancers.
If someone has tumor genetic testing that reveals the presence of a harmful BRCA1 or BRCA2 variant in the tumor, they should consider having a germline genetic (blood) test to determine if the variant was inherited. Knowing if the variant was inherited is important for that individual to understand their risks to potentially develop other cancers in the future. It can also determine if other family members may be at risk of inheriting the harmful variant.