BRCA2 is a critical tumor suppressor gene that functions primarily in homologous recombination DNA repair by facilitating RAD51 assembly onto single-stranded DNA and stabilizing RAD51-DNA filaments. The protein binds selectively to single-stranded DNA and plays essential roles in replication fork processing, centrosome duplication, and preventing R-loop-associated genomic instability. Germline pathogenic variants in BRCA2 confer substantially elevated lifetime risks for breast cancer (up to 80%) and ovarian cancer (up to 40%), with carriers also showing increased risks for prostate, pancreatic, and other cancers 1. Among premenopausal women with breast cancer, BRCA2 carriers face a 27% 10-year cumulative risk of contralateral breast cancer 2. BRCA2-deficient tumors exhibit distinct mutational landscapes and immune microenvironments compared to BRCA1-deficient tumors, with BRCA2 mutations associated with superior responses to immune checkpoint blockade therapy 3. Clinically, BRCA2 alterations serve as biomarkers for PARP inhibitor sensitivity, with olaparib demonstrating efficacy in metastatic castration-resistant prostate cancer patients harboring BRCA2 alterations detected through circulating tumor DNA testing 4. Population-based BRCA2 testing has proven cost-effective compared to family history-based approaches, potentially preventing thousands of additional breast and ovarian cancers 5. At the population level, gnomAD v4.1 classifies this gene as LoF-tolerant because heterozygous carriers are viable; this is distinct from clinical pathogenicity in disease contexts.