ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3226C>G (p.Arg1076Gly) (rs63750617)

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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 RCV000491655 SCV000580189 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504512 SCV000592627 uncertain significance Lynch syndrome 2012-11-20 criteria provided, single submitter clinical testing
Invitae RCV000629920 SCV000750876 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1076 of the MSH6 protein (p.Arg1076Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs63750617, ExAC 0.001%). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 428337). 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. A different missense substitution at this codon (p.Arg1076Cys) has been determined to be pathogenic (PMID: 15483016, 16418736, 16525781, 21039432, 18409202). This suggests that the arginine residue is critical for MSH6 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759862 SCV000889488 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing

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