ClinVar Genomic variation as it relates to human health

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic, esophageal, and other cancers, but also in healthy controls (Momozawa et al., 2018; Ohmoto et al., 2018; Deng et al., 2019; Chen et al., 2020; Dorling et al., 2021; Wagener et al., 2022); This variant is associated with the following publications: (PMID: 30826992, 36468172, 19782031, 22419737, 30833958, 30287823, 26928463, 27997549, 34570441, 36243179, 32091409, 33471991, 32566746, 31867841, 29667044, 37377590)

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Variant summary: CHEK2 c.755G>A (p.Ser252Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 298804 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.755G>A has been reported in the literature in individuals affected with pancreatic cancer, breast cancer, or Esophageal squamous cell carcinoma (Ohmoto_2018, Momozawa_2018, Deng_2019, Chen_2019). A large case-control study in Japanese patients with breast cancer showed that odds ratio of this variant is 1.4 (95%CI=0.6-3.1), suggesting that this variant is unlikely to associate with the disease. Co-occurrence with a pathogenic variant has been reported (TP53 c.743G>A , p.Arg248Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign.