Germline variant spectrum of hereditary cancer susceptibility genes in a Chinese cohort

Hereditary cancers, caused by germline pathogenic variants in cancer susceptibility genes, account for 5%∼10% of malignancies globally. However, their prevalence and genetic spectrum in the Chinese population remain poorly characterized. This study aimed to investigate germline pathogenic variants in 21 cancer susceptibility genes within a Chinese cohort undergoing routine health examinations. Targeted sequencing of 21 cancer predisposition genes in 10,456 cancer-free Chinese adults (mean age 44.0 ± 10.1 years; male: 60.52%, n = 6328; female: 39.48%, n = 4128) identified pathogenic/likely pathogenic germline variants in 1.57% (164/10,456) of participants. BRCA2 (38 variants), MUTYH (29 variants), and ATM (28 variants) accounted for 58.5% of all pathogenic variants. Eight novel pathogenic variants were validated in ATM, BRCA1, BRCA2, CHEK2, MUTYH, and PALB2. Non-Han ethnic groups showed 4.56-fold higher carrier rates than Han Chinese (5.70% vs 1.25%; χ2 = 89.77, p < 0.001). Only 6.1% of variant carriers pursued genetic counseling despite 49.39% reporting family cancer history. This study reveals clinically significant germline cancer predisposition in 1.57% of asymptomatic Chinese adults, with substantial ethnic disparities. Crucially, we identified eight novel pathogenic variants across six cancer susceptibility genes, all unreported in gnomAD/ClinVar and computationally predicted as deleterious. The 93.9% non-engagement in genetic counseling highlights the imperative for evidence-based interventions; including provider education initiatives to advance precision prevention.