BRCA1 and BRCA2 Mutations

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 potentially harmful BRCA mutations varies by population. The estimated prevalence is 0.2% to 0.3% in the general population of women, 6.0% in women with cancer onset before age 40 years, and 2.1% in the general population of Ashkenazi Jewish women.

A woman's risk for breast cancer increases to 45% to 65% by age 70 years if she has clinically significant mutations in either BRCA gene. The risk of developing contralateral breast cancer is 83% for BRCA1 and 62% for BRCA2. Mutations in the BRCA1 gene increase ovarian cancer risk to 39% by age 70 years, and mutations in the BRCA2 gene increase ovarian cancer risk to 10% to 17% by age 70 years. 

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.

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 an affected family member with a BRCA-related cancer is not available then the relative with the highest probability of mutation should be tested. 

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 no risk-reduction strategies are available. Once these children become adults they may want to obtain genetic counseling to discuss the merits of genetic testing.

The type of mutation analysis required depends on family history. Individuals from families with known mutations or from ethnic groups in which certain mutations are more common (e.g., Ashkenazi Jewish women) can be tested for these specific mutations. 

Individuals of Ashkenazi Jewish descent are usually tested for the three founder mutations; c.185delAG and c.5385insC in BRCA1, and c.6174delT in BRCA2. Next generation 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. 

Testing for BRCA1 and BRCA2 mutations identifies both benign and pathogenic genetic variants. Variants are classified as known, predicted, or possible pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Approximately 15 to 20% of variants likely to cause cancer and 3 to 4% are of unknown significance. 

Interpreting BRCA1 and BRCA2 variants is challenging. The BRCA exchange is a website that was created as a central repository of more than 20,000 unique BRCA1 and BRCA2 variants. The International Evidence- based Network for the Interpretation of Germline Mutant Alleles Consortium provides expert classification of more than 6100 of those variants. So far, 3700 are classified as pathogenic. BRCA Exchange is available at https://brcaexchange.org. An app is also available for Android and Apple devices. 

Depending on the variant, clinicians and patients essentially have 3 options:

• A preventive approach such as breast or ovary removal for patients with a pathogenic variant.
• Targeted therapies for patients with a cancer diagnosis associated with a pathogenic variant.
• Periodically reappraising patients with variants of uncertain clinical significance.

Management decisions should not be based on variants of unknown significance.

Specimen requirement is a lavender or yellow top tube of blood. 

References

Richards S, Aziz N, Bale S, et al: Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 May;17(5):405-424.

NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast and Ovarian Version 1.2015.  Available at www.nccn.org

Voelker R. Taking the Uncertainty Out of Interpreting BRCA Variants. JAMA. Published online March 20, 2019.