BRCA1/2 variant landscape and clinical correlates in high-risk breast cancer patients from Eastern China.

Global advances in genetic testing are reshaping breast cancer management. Although large unselected Chinese cohorts have been reported, the BRCA1 and BRCA2 (BRCA1/2) variant landscape specifically in high-risk, clinically referred populations remains poorly characterized. We aimed to delineate the landscape of BRCA1/2 variants in high-risk Chinese breast cancer patients, consistent with the clinical referral and testing pathway, and to provide evidence to inform risk-adapted clinical practice for high-risk patients with breast cancer in eastern China. We analyzed 1,262 high-risk Chinese breast cancer patients using targeted next-generation sequencing to detect BRCA1/2 germline variants. Variant clinical significance was interpreted primarily based on ClinVar annotations within the ACMG-AMP 2015 framework, with population frequency and in silico prediction results used as supporting evidence. Statistical analyses were performed in R (version 4.5.0). In total, 124 cases were identified as carriers of 81 BRCA1/2 P/LP (pathogenic or likely pathogenic) variants. P/LP carriers were more frequent in patients aged ≤45 years in our cohort. A total of 9.8% of patients carried BRCA1/2 P/LP variants, with 5.5% and 4.3% carrying BRCA1 and BRCA2 variants (70 vs. 54 cases), respectively. Among the 336 patients with triple-negative breast cancer (TNBC), 60 cases carried BRCA1/2 P/LP variants (51 BRCA1 vs. 9 BRCA2). A total of 21 variants were observed in more than one participant, including BRCA1 c.5470_5477del, a founder mutation in Chinese populations. Taken together, this study provides the most comprehensive characterization to date of the BRCA1/2 variant landscape in a high-risk Chinese breast cancer cohort from mainland China, offering population-specific reference data to refine genetic counseling, screening prioritization, and risk management, with potential implications for targeted prevention and intervention in Chinese patients seen in clinical practice.