Prevalence of germline CHEK2 variants in East Asians and Koreans based on population genomic databases

Abstract

Checkpoint kinase 2 (CHEK2) encodes a serine/threonine kinase involved in the DNA damage response through ATM-Chk2-p53 signaling. Its function in maintaining genomic stability classifies it as a tumor suppressor. Heterozygous germline pathogenic variants in CHEK2 are associated with a moderate increase in lifetime risk of breast and prostate cancer. This study assessed the prevalence of CHEK2 variants globally, with a focus on East Asian and Korean populations, for which data have remained limited. We analyzed 125,748 exomes from the Genome Aggregation Database (gnomAD), including 9,197 East Asians, along with additional data from 5,305 individuals in the Korean Variant Archive, 3,617 in Korea4K, and 1,722 in the Korean Reference Genome Database. All CHEK2 variants were classified according to guidelines established by the American College of Medical Genetics, Genomics, and Clinical Genome Resources. The global prevalence of CHEK2 variants was 0.76%, with the highest observed in the Finnish population (2.04%) and the lowest in East Asians (0.11%). By integrating data from Korean genomic databases and gnomAD, representing a total of 12,553 Korean individuals, the overall prevalence in the Korean population was estimated at 0.13%. These findings represent the first integrated estimate of CHEK2 variant frequency in Koreans using multiple population-specific genomic datasets. The results provide a useful reference for future studies and highlight the need for region-specific genetic research to inform counseling and hereditary cancer risk management.