ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3188T>G (p.Leu1063Arg) (rs1060502901)

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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 RCV000491375 SCV000580251 likely pathogenic Hereditary cancer-predisposing syndrome 2014-10-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000623149 SCV000740672 pathogenic Lynch syndrome I 2018-03-09 reviewed by expert panel curation Class 5 - Pathogenic Classification using multifactorial probability: 0.9978
Invitae RCV000468032 SCV000551112 uncertain significance Lynch syndrome 2016-10-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 1063 of the MSH6 protein (p.Leu1063Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with colorectal cancer and Lynch syndrome (PMID: 23733757, 26099011). This variant has also been reported to segregate in a family affected with colorectal cancer and/or polyps in the Leiden Open-source Variation Database (PMID: 21520333), however, the evidence provided for this family is insufficient to definitively conclude whether this variant segregates with disease or not. 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. In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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