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BRCA1 and BRCA2 Mutations

Breast cancer is the most common cancer in women in the United States and the second leading cause of cancer death in women. Ovarian cancer is the fifth leading cause of cancer death in women in the United States. Mutations of the BRCA genes account for 5% to 10% of breast cancer cases and 15% of ovarian cancer cases.

BRCA1 and BRCA2 are human genes that code for tumor suppressor genes. Individuals with BRCA1 or BRCA2 mutations have markedly increased susceptibility to breast and ovarian cancer. They are inherited as autosomal dominant germline mutations with high penetrance. Mutations in the BRCA1 and BRCA2 genes account for approximately 5 percent of all breast cancer cases. Most women with breast or ovarian cancer have a sporadic rather than an inherited cancer.

The prevalence of BRCA1 and BRCA2 deleterious mutations varies among ethnic groups and geographic regions. BRCA1 and BRCA2 mutations occur in approximately 1 in 40 people in people of Ashkenazi Jewish descent. Three founder mutations in BRCA1 and BRCA2 account for almost 90 percent of the mutations identified in these individuals. Incidence is also higher in Icelandic, French Canadian and United States Hispanic populations. BRCA1 and BRCA2 mutations are less common in the general population, occurring in 1 in 300 to 1 in 500 individuals.

The lifetime risk of breast cancer is generally estimated to be higher with BRCA1 than BRCA2 mutations. The lifetime risk of a carrier developing breast cancer by age 70 is 60% for BRCA1 and 55% for BRCA2. The risk of developing contralateral breast cancer is 83% for BRCA1 and 62% for BRCA2. The risk of developing ovarian cancer is 59% for BRCA1 and 17% for BRCA2 mutation by age 70.

Men with a BRCA1 or BRCA2 mutation also have an increased susceptibility to breast cancer. The risk is greater with BRCA2 than BRCA1 mutations. Lifetime risk of breast cancer is 6 percent in men with a BRCA2 gene mutation, 1 percent with BRCA1 mutation and 0.1 percent in the general population

Triple negative breast cancers (TNBC) are tumors which test negative for estrogen and progesterone receptors and HER2 expression. They account for approximately 15 to 20 percent of all breast cancer diagnoses. Ten to 20 percent of women with TNBC have a BRCA1 mutation. Because of this high frequency, NCCN guidelines recommend that women with TNBC, who are age 60 or younger, should be offered BRCA1 and 2 counseling and testing regardless of their ethnicity and family history.

Mutations in the BRCA genes cluster in families with an autosomal dominant pattern of transmission. Genetic risk assessment and BRCA mutation testing is a multistep process that begins with identifying patients with family or personal histories of breast or ovarian cancer; family members with known harmful BRCA mutations; or ethnicity associated with harmful BRCA mutations.

Several familial risk stratification tools are available for primary care physicians to assess the likelihood of BRCA mutations and determine the need for genetic counseling. Examples include the Ontario Family History Assessment Tool, Manchester Scoring System, Referral Screening Tool, Pedigree Assessment Tool, FHS-7, and brief versions of BRCAPRO.

The United States Preventive Services Task Force recommended 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 mutation in BRCA1 or BRCA2 genes.

Risk factors that are associated with an increased likelihood of having a harmful mutation in BRCA1 or BRCA2, include:

  • Breast cancer diagnosed before age 50 years
  • Cancer in both breasts
  • Both breast and ovarian cancers
  • Multiple breast cancers
  • 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 is most expeditious to first test an affected family member. If that person is found to have a BRCA1 or BRCA2 mutation, then other family members may want to visit with a genetic counselor to determine if they should be tested. If it is not possible to test an affected family member, men and women with a family history suggestive of inherited cancer should seek out genetic counseling to determine the need for testing.

Individuals with an unknown family history who do not have an early-onset cancer or male breast cancer are at very low risk of having a harmful BRCA1 or BRCA2 mutation and are unlikely to benefit from routine genetic testing.

Professional societies do not recommend testing of children, even those with a family history, because their risk of developing cancer is very low and there are no risk-reduction strategies exist. Once these children become adults they may want to obtain genetic counseling to discuss the merits of genetic testing.

Individuals of Ashkenazi Jewish descent are usually tested for the three founder mutations, which costs approximately $475. Gene sequencing is required to detect the numerous mutations that may occur in the general population. This testing is much more expensive, ranging between $2000 and $4000. Most insurance will not pay for testing of individuals who do not have a family history suggestive of an inherited risk of breast cancer.

Tests for BRCA mutations are highly sensitive and specific for known mutations, but interpretation of results is complex and requires posttest counseling. Guidelines from the American College of Medical Genetics and Genomics, which were updated in 2015, recommend new standard terminology for reporting BRCA mutations identified by genetic tests. These include a 5-tier terminology system using the terms pathogenic, likely pathogenic, uncertain significance, likely benign, and benign. Women at increased risk of breast cancer should be offered risk-reducing medications such as tamoxifen, raloxifene, or aromatase inhibitors to women at increased risk for breast cancer.

Most laboratories detect a BRCA1 or BRCA2 variant of unknown clinical significance in approximately 4 percent of individuals. Medical management should not be based on these variants.


Brody LC, Biesecker BB. Breast cancer susceptibility genes. BRCA1 and BRCA2. Medicine (Baltimore). 1998;77(3):208-226.

Mersch J, Jackson MA, Park M, et al. Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian. Cancer. 2015;121(2):269-275.

Antoniou A, Pharoah PD, Narod S, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003;72(5):1117-1130.

Chen S, Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. N Engl J Med. 2007;25(11):1329-1333.

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