Clinical implications of the type and genomic location of pathogenic BRCA1 and BRCA2 variants in hereditary breast and ovarian cancer

Germline pathogenic or likely pathogenic variants (P/LPVs) in BRCA1 and BRCA2 are major determinants of hereditary breast and ovarian cancer susceptibility. Although clinical management has traditionally relied on the presence of a BRCA1/BRCA2 alteration regardless of its specific characteristics, growing evidence suggests that not all BRCA P/LPVs are biologically and clinically equivalent. Variant location within BRCA1 and BRCA2 influences the relative distribution of breast and ovarian cancer risk. Breast cancer cluster regions (BCCRs) are associated with a higher relative risk of breast versus ovarian cancer, whereas ovarian cancer cluster regions (OCCRs), largely encompassing exon 11, are associated with a relative shift toward ovarian cancer risk. Variant type may also be clinically relevant. Protein-truncating P/LPVs have been associated with higher cancer risks than selected missense variants with residual protein function and lower penetrance. Some studies have also reported poorer outcomes for carriers of protein-truncating P/LPVs and more favorable outcomes for those with missense variants. In this narrative review, we summarize current evidence on the clinical implications of BRCA1/BRCA2 P/LPV type and genomic location. While associations between variant location and breast or ovarian cancer risk are supported by large international consortia, prognostic and predictive associations remain largely exploratory. A better understanding of variant-specific genotype-phenotype correlations may ultimately refine risk prediction, preventive strategies, and treatment selection in hereditary breast and ovarian cancer.