ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.58G>A (p.Val20Met)

dbSNP: rs1198168331
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000580093 SCV000685102 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-17 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 20 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001359880 SCV001555768 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-05 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 20 of the MSH2 protein (p.Val20Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 489946). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH2 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 RCV000580093 SCV002653649 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing The p.V20M variant (also known as c.58G>A), located in coding exon 1 of the MSH2 gene, results from a G to A substitution at nucleotide position 58. The valine at codon 20 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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