ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3104G>T (p.Arg1035Leu) (rs730881801)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160688 SCV000211309 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3104G>T at the cDNA level, p.Arg1035Leu (R1035L) at the protein level, and results in the change of an Arginine to a Leucine (CGA>CTA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a colorectal tumor (Ashktorab 2017). MSH6 Arg1035Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg1035Leu is located in the lever domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg1035Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000198759 SCV000254304 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-31 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 1035 of the MSH6 protein (p.Arg1035Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs730881801, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182641). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000223597 SCV000276589 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Insufficient or conflicting evidence
Color RCV000223597 SCV000685352 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175452 SCV001339018 uncertain significance not specified 2020-03-20 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3104G>T (p.Arg1035Leu) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 248120 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, no occurrence of c.3104G>T in the germline state was reported in individuals affected with Lynch Syndrome, and no experimental evidence demonstrating its impact on protein function have been published. Four 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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