BRCA2

BRCA2 encodes a protein essential for homologous recombination repair of DNA double-strand breaks, working alongside RAD51 and BRCA1 to maintain genomic stability. Unlike BRCA1, BRCA2 mutations carry a higher relative risk for male breast cancer and pancreatic cancer, and are associated with Fanconi anemia (biallelic BRCA2/FANCD1 mutations) in a subset of patients. BRCA2 mutation carriers have an estimated 45-85% lifetime risk of breast cancer and 10-20% risk of ovarian cancer, though risks are somewhat lower than BRCA1 for ovarian cancer specifically. BRCA2-associated breast cancers tend to be more commonly ER-positive compared to BRCA1-associated cancers, which are more frequently triple-negative. Increased risk also exists for prostate cancer (particularly aggressive, higher Gleason score disease), pancreatic cancer, and melanoma. Testing is recommended for individuals with strong family history of breast/ovarian cancer, Ashkenazi Jewish ancestry (founder mutations exist), male breast cancer, or early-onset disease. Management includes enhanced surveillance (mammography, MRI), risk-reducing surgery (prophylactic mastectomy, salpingo-oophorectomy), and chemoprevention. Clinically important: PARP inhibitors (olaparib, talazoparib) exploit synthetic lethality in BRCA-mutated tumors deficient in homologous recombination, causing accumulation of unrepaired DNA damage and cell death—a key USMLE pharmacology concept.