Prevalence of germline pathogenic variants in cancer predisposition genes in the Japanese population

Germline pathogenic variants (GPVs) in cancer predisposition genes increase cancer risk, but their population-level prevalence in Japan remains unclear.

To estimate the prevalence of GPV carriers of hereditary cancer predisposition syndromes (HCPSs) in the Japanese population.

A cross-sectional analysis of the Tohoku Medical Megabank Organization datasets was conducted to assess allele frequencies of rare GPVs, estimate carrier prevalence, and describe variant distribution.

The cumulative allele frequency of rare GPVs of cancer predisposing genes was 1.47% for autosomal dominant and 3.20% for autosomal recessive diseases. The estimated prevalence of GPV carriers was 2.90% (1 in 35 individuals) and 0.10% (1 in 977 individuals) for autosomal dominant HCPSs and autosomal recessive HCPSs, respectively; ~6.19% of the population (1 in 16 individuals) were carriers. Variant types differed across genes, and hotspot variants had a significant impact on allele frequencies. Moreover, 47 structural variants (0.28%) having the potential to cause structural disruption were identified.

Allele frequency analysis of rare GPVs of cancer predisposition genes offered valuable insight into the prevalence of GPV carriers of HCPSs in the Japanese population. Hotspot variants may represent founder mutations within specific ethnic groups, and their presence or absence could affect gene-specific allele frequencies.