ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.7G>A (p.Val3Met)

dbSNP: rs1257347271
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000706952 SCV000836027 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-08-29 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 3 of the MSH2 protein (p.Val3Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 582790). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) 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.
Color Diagnostics, LLC DBA Color Health RCV000776681 SCV000912307 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-05 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 3 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders 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.
Ambry Genetics RCV000776681 SCV002678668 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-16 criteria provided, single submitter clinical testing The p.V3M variant (also known as c.7G>A), located in coding exon 1 of the MSH2 gene, results from a G to A substitution at nucleotide position 7. The valine at codon 3 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly 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.
Baylor Genetics RCV003460988 SCV004196286 uncertain significance Lynch syndrome 1 2023-08-26 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003999779 SCV004826194 uncertain significance Lynch syndrome 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 3 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders 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.

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