ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3470G>A (p.Gly1157Asp)

dbSNP: rs752212361
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000758614 SCV000887371 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.3470G>A has a 93.3% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Color Diagnostics, LLC DBA Color Health RCV001175727 SCV001339437 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV001175727 SCV002613940 pathogenic Hereditary cancer-predisposing syndrome 2021-08-18 criteria provided, single submitter clinical testing The p.G1157D variant (also known as c.3470G>A), located in coding exon 6 of the MSH6 gene, results from a G to A substitution at nucleotide position 3470. The glycine at codon 1157 is replaced by aspartic acid, an amino acid with similar properties. In one functional study, this variant demonstrated deficient mismatch repair activity in an in vitro complementation assay (Drost M et al. Genet Med, 2020 05;22:847-856). Based on internal structural analysis using published crystal structures, G1157D disrupts the local structure in the ATPase domain (Warren JJ et al. Mol Cell, 2007 May;26:579-92; Ambry internal data). Another alteration at the same codon, p.G1157C (c.3469G>T), has been identified in several individuals whose Lynch-associated tumor demonstrated high microsatellite instability (MSI-H) and/or isolated loss of MSH6 protein expression on immunohistochemistry (IHC) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc. RCV003453547 SCV004189307 likely pathogenic Lynch syndrome 5 2023-08-23 criteria provided, single submitter clinical testing This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31965077]. This variant is expected to disrupt protein structure [Myriad internal data].

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