Prevalence and Reclassification of BRCA1 and BRCA2 Variants in a Large Unselected Chinese Han Breast Cancer Cohort

Background: Accurate interpretation of BRCA1/2 variants is critical for risk assessment, enhanced cancer surveillance, prevention strategies, and precise clinical treatment of breast cancer. However, current worldwide standards depend primarily on sequencing information from Caucasian populations. Methods: Panel-based sequencing served to detect BRCA1/2 variants in a Chinese multicenter cohort of 21,216 breast cancer patients (BCs) and 6,434 healthy controls (HCs). Findings: 1,245 pathogenic variants of BRCA1/2, 262 of which were novel (21.04%), and 2,517 variants of uncertain significance (VUS) were identified. Unlike in the Caucasian population, BRCA2 variants were more frequent than BRCA1 variants (56.34% versus 43.66%). The 48 most common variants accounted for 39.86% of all pathogenic variants, and were not reported as common variants in Caucasians. Furthermore, we unambiguously reclassified VUS in 508 subjects, lowering the VUS ratio from 9.05% to 7.21%. Pathogenic BRCA1/2 variants correlated with younger onset age, higher frequencies of bilateral and triple-negative BC, invasive carcinomas, high histological grades, and family history of BC and other cancers. Interpretation: Strong ethnicity-specific occurrences of pathogenic BRCA1/2 variants were identified in the Chinese population. Hence, the findings provide rationale and sequencing information for the implementation of BRCA1/2 variants tailored to the Chinese population into clinical risk assessment. Funding Statement: National Natural Science Foundation of China 81772802, Shanghai science and technology innovation action plan of China 17JC1404400 and 16DZ19102, Special Funds for Technological Innovation of Shanghai Jiao Tong University YG2016MS22, Chinese Academy of Science XDA12020223 (W.H.X), Natural Science Foundation of Zhejiang Province LZ16H160002 (C.Y.D), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents (C.Y.D). Declaration of Interests: Authors declare no potential conflicts of interest. Ethics Approval Statement: The study was approved by the Ethics Committee of all the hospitals involved and was performed according to the Declaration of Helsinki Principles. Written consent to notify blood samples for future research was obtained for each patient under the Institutional Review Board (IRB)-approved protocol.