ClinVar Genomic variation as it relates to human health

This missense variant replaces lysine with asparagine at codon 494 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/233586 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 494 of the CHEK2 protein (p.Lys494Asn). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 420225). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 19782031, 22419737)

A variant of uncertain significance was detected in the CHEK2 gene (c.1482G>C). This sequence change replaces lysine with asparagine at codon 494 of the CHEK2 protein (p.Lys494Asn). This variant is not present in population databases (gnomAD). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 420225) with 6 submissions, all of which describe this variant as of uncertain significance. In-silico predictions show benign computational verdict based on 8 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, MVP, MutationAssessor, PrimateAI and SIFT vs 4 pathogenic predictions from FATHMM-MKL, LIST-S2, M-CAP and MutationTaster and the position is not highly conserved. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance.

Variant summary: CHEK2 c.1482G>C (p.Lys494Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-06 in 233586 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1482G>C has been reported in the literature in individuals affected with breast cancer, with a family history of breast and/or ovarian cancer, and in at least one individual with soft tissue sarcoma and a family history of cancer suggestive of Li-Fraumeni syndrome (Stolarova_2023, Valiante_2022). These reports do not provide unequivocal conclusions about association of the variant with hereditary breast and ovarian cancer syndrome. An experimental study using two complementary functional assays for quantification of the catalytic activity of CHK2 in vitro found no damaging effect of this variant compared to the WT protein (Stolarova_2023). ClinVar contains an entry for this variant (Variation ID: 420225). The following publications have been ascertained in the context of this evaluation (PMID: 37449874). Based on the evidence outlined above, the variant was classified as uncertain significance.

The variant c.1482G>C was reported in a case of soft tissue sarcoma with Li-Fraumeni syndrome. This variant is extremely rare and is located in an hot-spot mutation region.