ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1183G>A (p.Val395Ile)

dbSNP: rs587780170
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467802 SCV000550548 uncertain significance Familial cancer of breast 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 395 of the CHEK2 protein (p.Val395Ile). This variant is present in population databases (rs587780170, 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: 410061). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics RCV001010081 SCV001170229 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-28 criteria provided, single submitter clinical testing The p.V395I variant (also known as c.1183G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1183. The valine at codon 395 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly 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.
PreventionGenetics, part of Exact Sciences RCV003932711 SCV004761511 uncertain significance CHEK2-related condition 2024-01-22 criteria provided, single submitter clinical testing The CHEK2 c.1183G>A variant is predicted to result in the amino acid substitution p.Val395Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is reported in ClinVar database as a variant of unknown significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/410061/). Alternative variant at this codone p.Val395Leu was previously reported in an individual with colorectal cancer and another individual with ovarian cancer (Yurgelun et al. 2017. PubMed ID: 28135145; Kleiblova et al. 2019. PubMed ID: 31050813, see supplementary table S3). However, a functional analysis of the p.Val395Leu variant protein in a yeast model indicated that this change may be benign (Delimitsou et al. 2019. PubMed ID: 30851065). At this time, the clinical significance of variant p.Val395Ile is uncertain due to the absence of conclusive functional and genetic evidence.

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