ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1229G>T (p.Gly410Val)

gnomAD frequency: 0.00001  dbSNP: rs1354753753
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567171 SCV000669707 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-01 criteria provided, single submitter clinical testing The p.G410V variant (also known as c.1229G>T), located in coding exon 7 of the MSH2 gene, results from a G to T substitution at nucleotide position 1229. The glycine at codon 410 is replaced by valine, an amino acid with dissimilar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is not 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000812381 SCV000952692 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-09-06 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004001031 SCV004832646 uncertain significance Lynch syndrome 2023-10-02 criteria provided, single submitter clinical testing This missense variant replaces glycine with valine at codon 410 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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