Genetic Testing for BRCA1 and BRCA2

by National Cancer Institute

What are BRCA1 and BRCA2?

Each year, more than 192,000 American women learn they have breast cancer. Approximately 5 to 10 percent of these women have a hereditary form of the disease. Changes, called alterations or mutations, in certain genes make some women more susceptible to developing breast and other types of cancer. Inherited alterations in the genes called BRCA1 and BRCA2 (short for breast cancer 1 and breast cancer 2) are involved in many cases of hereditary breast and ovarian cancer. Researchers are searching for other genes that may also increase a woman's cancer risk.

The likelihood that breast and/or ovarian cancer is associated with BRCA1 or BRCA2 is highest in families with a history of multiple cases of breast cancer, cases of both breast and ovarian cancer, one or more family members with two primary cancers (original tumors at different sites), or an Ashkenazi (Eastern European) Jewish background. However, not every woman in such families carries an alteration in BRCA1 or BRCA2, and not every cancer in such families is linked to alterations in these genes.

How do alterations in BRCA1 and BRCA2 affect a person's risk of cancer?

A woman's lifetime chance of developing breast and/or ovarian cancer is greatly increased if she inherits an altered BRCA1 or BRCA2 gene. Women with an inherited alteration in one of these genes have an increased risk of developing these cancers at a young age (before menopause), and often have multiple close family members with the disease. These women may also have an increased chance of developing colon cancer.

Men with an altered BRCA1 or BRCA2 gene also have an increased risk of breast cancer (primarily if the alteration is in BRCA2), and possibly prostate cancer. Alterations in the BRCA2 gene have also been associated with an increased risk of lymphoma, melanoma, and cancers of the pancreas, gallbladder, bile duct, and stomach in some men and women.

According to estimates of lifetime risk, about 13.2 percent (132 out of 1,000 individuals) of women in the general population will develop breast cancer, compared with estimates of 36 to 85 percent (360-850 out of 1,000) of women with an altered BRCA1 or BRCA2 gene. In other words, women with an altered BRCA1 or BRCA2 gene are 3 to 7 times more likely to develop breast cancer than women without alterations in those genes. Lifetime risk estimates of ovarian cancer for women in the general population indicate that 1.7 percent (17 out of 1,000) will get ovarian cancer, compared with 16 to 60 percent (160-600 out of 1,000) of women with altered BRCA1 or BRCA2 genes. No data are available from long-term studies of the general population comparing the cancer risk in women who have a BRCA1 or BRCA2 alteration with women who do not have an alteration in these genes. Therefore, these figures are estimated ranges that may change as more research data are added.

Some evidence suggests that there are slight differences in patterns of cancer between people with BRCA1 alterations and people with BRCA2 alterations, and even between people with different alterations in the same gene. For example, one study found that alterations in a certain part of the BRCA2 gene were associated with a higher risk for ovarian cancer in women, and a lower risk for prostate cancer in men, than alterations in other areas of BRCA2.

Most research related to BRCA1 and BRCA2 has been done on large families with many affected individuals. Estimates of breast and ovarian cancer risk associated with BRCA1 and BRCA2 alterations have been calculated from studies of these families. Because family members share a proportion of their genes and, often, their environment, it is possible that the large number of cancer cases seen in these families may be partly due to other genetic or environmental factors. Therefore, risk estimates that are based on families with many affected members may not accurately reflect the levels of risk in the general population.

Are specific alterations in BRCA1 and BRCA2 more common in certain populations?

Specific gene alterations have been identified in different ethnic groups. For example, among individuals of Ashkenazi Jewish descent, researchers have found that about 2.3 percent (23 out of 1,000 persons) have an altered BRCA1 or BRCA2 gene. This frequency is about 5 times higher than that of the general population. Among people with alterations in BRCA1 or BRCA2, three particular alterations have been found to be most common in the Ashkenazi Jewish population — two in the BRCA1 gene and one in the BRCA2 gene. It is not known whether the increased frequency of these alterations is responsible for the increased risk of breast cancer in Jewish populations compared with non-Jewish populations. Other ethnic and geographic populations, such as the Norwegian, Dutch, and Icelandic people, also have a higher rate of certain genetic alterations in BRCA1 and BRCA2. This information about genetic differences between ethnic groups may help health care providers determine the most appropriate genetic test to select.

What does a positive BRCA1 or BRCA2 test result mean?

In a family with a history of breast and/or ovarian cancer, it may be most informative to first test a family member who has the disease. If that person is found to have an altered BRCA1 or BRCA2 gene, the specific change is referred to as a "known mutation." Other family members can then be tested to see if they also carry that specific alteration. In this scenario, a positive test result indicates that a person has inherited a known mutation in BRCA1 or BRCA2 and has an increased risk of developing certain cancers, as described above. However, a positive result provides information only about a person's risk of developing cancer. It cannot tell whether cancer will actually develop — or when. It is also impossible to predict the effectiveness of special screening or preventive medical procedures for people with alterations in BRCA1 or BRCA2. Not all women who inherit an altered gene will develop breast or ovarian cancer.

A positive test result may have important health and social implications for family members, including future generations. Unlike most other medical tests, genetic tests can reveal information not only about the person being tested, but also about that person's relatives. Both men and women who inherit an altered BRCA1 or BRCA2 gene, whether or not they get cancer themselves, may pass the alteration on to their sons and daughters. However, not all children of people who have an altered gene will inherit the alteration.

What does a negative BRCA1 or BRCA2 test result mean?

A negative test result will be interpreted differently, depending upon whether there is a known mutation in the family. If someone in a family has a known mutation in BRCA1 or BRCA2, testing other family members for that specific gene alteration can provide information about their cancer risk. In this case, if a family member tests negative for the known mutation in that family, it is highly unlikely that they have an inherited susceptibility to cancer. This test result is called a "true negative." Having a true negative test result does not mean that a person will not get cancer; it means that the person's risk of cancer is the same as that of the general population.

In cases where no known mutation in BRCA1 or BRCA2 has previously been identified in a family with a history of breast and/or ovarian cancer, a negative test is not informative. It is not possible to tell whether a person has an alteration in BRCA1 or BRCA2 that was not identified by the test (a false negative), or whether the result is a true negative. In addition, it is possible for people to have an alteration in a gene other than BRCA1 or BRCA2 that increases their cancer risk, but is not detectable by this test.

What does an ambiguous BRCA1 or BRCA2 test result mean?

If the test shows a change in BRCA1 or BRCA2 that has not been associated with cancer in other people, that person's test result may be interpreted as ambiguous or uncertain. One study found that 10 percent of women who underwent BRCA1 and BRCA2 testing had this type of ambiguous genetic change. Because everyone has genetic alterations that do not increase the risk of disease, it is sometimes not known whether a specific change affects a person's risk of developing cancer. As more research is conducted and more people are tested for BRCA1 or BRCA2 alterations, scientists will learn more about these genetic alterations and cancer risk.

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