ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132174 SCV000187253 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-22 criteria provided, single submitter clinical testing Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Invitae RCV000541079 SCV000624872 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-05 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 not been reported in the literature in individuals with MSH6-related conditions. 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 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 RCV000132174 SCV000685408 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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