ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1291A>G (p.Arg431Gly)

gnomAD frequency: 0.00001  dbSNP: rs1064793470
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486280 SCV000566202 uncertain significance not provided 2018-10-18 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1291A>G at the cDNA level, p.Arg431Gly (R431G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Arg431Gly was not observed in large population cohorts (Lek 2016). This variant is located within the protein kinase domain (Cai 2009, Roeb 2012) In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether CHEK2 Arg431Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000528303 SCV000633118 uncertain significance Familial cancer of breast 2023-05-08 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. ClinVar contains an entry for this variant (Variation ID: 418842). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 431 of the CHEK2 protein (p.Arg431Gly).
Ambry Genetics RCV002383909 SCV002690877 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-11 criteria provided, single submitter clinical testing The p.R431G variant (also known as c.1291A>G), located in coding exon 11 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1291. The arginine at codon 431 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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