The prevalence and spectrum of germline mutations in BRCA1 and BRCA2 have been reported in single populations, with the majority of reports focused on White in Europe and North America. The Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) has assembled data on 18,435 families with BRCA1 mutations and 11,351 families with BRCA2 mutations ascertained from 69 centers in 49 countries on six continents. This study comprehensively describes the characteristics of the 1,650 unique BRCA1 and 1,731 unique BRCA2 deleterious (disease‐associated) mutations identified in the CIMBA database. We observed substantial variation in mutation type and frequency by geographical region and race/ethnicity. In addition to known founder mutations, mutations of relatively high frequency were identified in specific racial/ethnic or geographic groups that may reflect founder mutations and which could be used in targeted (panel) first pass genotyping for specific populations. Knowledge of the population‐specific mutational spectrum in BRCA1 and BRCA2 could inform efficient strategies for genetic testing and may justify a more broad‐based oncogenetic testing in some populations.

Testing women with TN breast cancers who were younger than 50 years for BRCA mutations is a cost-effective strategy and should be adopted into current guidelines for genetic testing.

Background Germline TP53 mutations predispose to early onset breast cancer (BC) in women and are associated with the Li Fraumeni syndrome. Published data on the pathological characteristics of breast cancer among women with TP53 mutations is limited. Methods We retrospectively reviewed clinical records of women who had genetic testing for suspected germline TP53 mutations and who were diagnosed with BC between 2000 to 2011. The pathological characteristics of the breast tumors from women testing positive (cases) for a mutation were compared to those testing negative (controls). Results Patients who tested positive for germline TP53 mutations (N=30) were compared to (N=79) controls. Human epidermal growth factor receptor 2 (HER2) amplification and/or overexpression was found in 67% of the tumors from the cases, compared to 25% for the controls (p=0.0001). Among patients with a mutation, 70% had estrogen receptor and/or progesterone receptor positive tumors, compared to 68% in the control group (p= 0.87). After adjusting for age at BC diagnosis, having a HER2 positive tumor increased the odds of testing positive for a germline TP53 mutation (OR, 6.9, 95% CI, 2.6 to 18.2). For each yearly increments in age at BC diagnosis, there was decreased likelihood of having a TP53 mutation by 5% (OR=0.95, CI 0.91 to 0.99). Conclusion This study suggests an association between germline TP53 mutations and early onset HER2 positive breast cancer. If confirmed in a larger cohort, these results could guide genetic testing strategies, lead to chemoprevention trials incorporating HER2 targeted therapies, and elucidate some of the molecular pathways involved in breast cancer.