ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3469G>T (p.Gly1157Cys) (rs587779264)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132174 SCV000187253 pathogenic Hereditary cancer-predisposing syndrome 2020-02-26 criteria provided, single submitter clinical testing The p.G1157C pathogenic mutation (also known as c.3469G>T), located in coding exon 6 of the MSH6 gene, results from a G to T substitution at nucleotide position 3469. The glycine at codon 1157 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration 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). Based on an internal structural assessment, this alteration disrupts the local structure in the ATPase domain (Warren JJ et al. Mol. Cell. 2007 May;26:579-92). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). 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.
Invitae RCV000541079 SCV000624872 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 1157 of the MSH6 protein (p.Gly1157Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 142773). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000132174 SCV000685408 likely pathogenic Hereditary cancer-predisposing syndrome 2021-02-10 criteria provided, single submitter clinical testing This missense variant replaces glycine with cysteine at codon 1157 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals affected with Lynch syndrome-associated cancers (Communication with external laboratory and ClinVar variation ID 142773). A different missense variant at this position, p.Gly1157Asp, has been reported to impact MSH6 function in DNA mismatch binding, in vitro mismatch repair and sensitivity to 6-thioguanine assays (PMID: 31965077). Three different amino acid substitutions, aspartic acid, serine and valine, in place of glycine 1157, have been observed in individuals affected with Lynch syndrome-associated cancers (PMID: 24323032, 31391288; Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174713 SCV001337984 uncertain significance not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3469G>T (p.Gly1157Cys) results in a non-conservative amino acid change located in the C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251390 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, there are no reports of c.3469G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating an impact on protein function in the literature. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV001267890 SCV001446378 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2020-07-31 no assertion criteria provided clinical testing

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