Genotype in BRCA ‐associated Breast Cancers

Women with BRCA 1 or 2 mutations are at high risk for breast cancer. For BRCA 1 , a trend of increasing risk has been associated with increasing downstream (3′) location for mutations compared to the upstream (5′) mutations in the gene. For BRCA 2 , an increased risk of breast cancer has been associated with mutations outside of the ovarian cancer cluster region ( OCCR ). We sought to determine the mutation position in BRCA ‐associated breast cancers and whether or not there was a genotype‐phenotype correlation. Breast cancer patients with BRCA 1/2 mutations were identified by a search of a prospectively maintained data base. Mutation site, patient, and tumor characteristics were determined through retrospective review. One hundred and sixty‐four patients with BRCA 1 ‐associated breast cancer and 109 patients with BRCA 2 ‐associated breast cancer were identified. Among patients with BRCA 1 ‐associated cancers, 86 (52%) had mutations in the 5′ half of the gene. Among patients with BRCA 2 ‐associated breast cancers, 40 (37%) had OCCR mutations. Although BRCA 1 ‐associated tumors were more likely to be ER / PR ‐ than BRCA 2 ‐associated cancers (p < 0.0001), there was no difference in the tumor characteristics among BRCA 1 or BRCA 2 ‐associated cancers based on mutation location. In this single‐institution study, over half of BRCA 1 ‐associated and over a third of BRCA 2 ‐associated breast cancers were associated with putative lower risk mutations. Although we cannot exclude the possibility that mutations in these regions confer a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize prevention strategies.