BRCAmutation

BRCA mutation refers to germline pathogenic variants in the BRCA1 or BRCA2 gene, which encode proteins that play a central role in homologous recombination, a high-fidelity DNA repair pathway. Loss of function in either gene predisposes cells to accumulate genetic damage, increasing cancer risk.

Inheritance is autosomal dominant, so a child has about a 50% chance of inheriting the mutation from an affected parent. Carriers may not develop cancer, but their overall lifetime risk for certain cancers is markedly elevated compared with the general population.

BRCA1 and BRCA2 mutations are most strongly associated with hereditary breast and ovarian cancer syndromes (HBOC). BRCA1 mutations confer substantial risk for breast and ovarian cancers, while BRCA2 mutations also raise breast cancer risk and confer higher risks for male breast cancer and pancreatic cancer. Risks vary by gene, family history, and ethnicity, with wide ranges reported for lifetime cancer probabilities.

Genetic testing and counseling are recommended for individuals with personal or family histories suggestive of HBOC. If a deleterious variant is found, cascade testing of at-risk relatives is advised. Management includes enhanced surveillance (earlier and more frequent MRI and mammography), and risk-reducing options such as mastectomy or salpingo-oophorectomy, which substantially lower cancer risk when appropriate timing is chosen.

Therapies for BRCA-mutant cancers increasingly include PARP inhibitors (for ovarian, breast, pancreatic, and prostate cancers) and platinum-based chemotherapy, reflecting tumor reliance on residual DNA repair pathways. Somatic BRCA mutations in tumors can also influence treatment choices.

Population notes include founder mutations in some groups (eg, certain Ashkenazi Jewish variants). The clinical interpretation of variants of uncertain significance remains a challenge in counseling and management.