Global prevalence and ethnic variation of pathogenic BRCA1/2 variants in breast cancer: a systematic review and meta-analysis

The breast cancer (BC) susceptibility genes 1 (BRCA1) and BC susceptibility genes 2 (BRCA2) are critical genes associated with hereditary breast cancer, and their mutation prevalence might greatly vary across different ethnic populations. This systematic review and meta-analysis evaluated global ethnic variation in BRCA1/2 mutation prevalence among breast cancer (BC) patients. We searched five databases for studies published between 2015 and 2025 that reported BRCA1/2 mutations in BC patients across various ethnic groups. 45 studies met the inclusion criteria, comprising about 44,000 BC patients. Data were stratified into two categories: (1) the frequency of all reported variants (including high-frequency polymorphisms) to assess global reporting patterns, and (2) the estimated clinical prevalence of confirmed Pathogenic and Likely Pathogenic (PLP) variants (excluding benign polymorphisms) for cancer risk assessment in broad ethnic categories (Asian, Chinese, Black/African descent, Hispanic/Latino, Middle Eastern/North African, European, Ashkenazi Jewish, and others). The prevalence of BRCA1/2 mutations in BC patients displayed substantial global variability. Heterogeneity was high (I² >95%, p < 0.001), reflecting diverse study populations and designs. The frequency of all reported variants varied substantially, reaching up to 17% in specific subgroups due to the inclusion of common polymorphisms. However, after strict filtering, the clinical prevalence of PLP variants ranged from < 1% to 5% in most ethnic groups, aligning with expected population risk. Ethnicity significantly influences BRCA1/2 mutation distribution among BC patients globally. These findings underscore the importance of population-tailored genetic testing approaches and the necessity of including underrepresented groups in genetic research to enhance risk assessment and personalized cancer care.