ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3649A>G (p.Arg1217Gly) (rs587780677)

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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 RCV000491291 SCV000580274 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000491291 SCV000911943 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
GeneDx RCV000657087 SCV000568731 uncertain significance not provided 2018-12-24 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3649A>G at the cDNA level, p.Arg1217Gly (R1217G) at the protein level, and results in the change of an Arginine to a Glycine (AGA>GGA). This variant has been observed in at least one woman with early onset, mismatch repair proficient cecal cancer as well as in a man with a personal and family history of prostate cancer (Leongamornlert 2014, Pearlman 2017). MSH6 Arg1217Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the ATPase domain and the binding site of Mg2+ (Kariola 2002, Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg1217Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122965 SCV000166232 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1217 of the MSH6 protein (p.Arg1217Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with family history of prostate cancer (PMID: 24556621). ClinVar contains an entry for this variant (Variation ID: 135842) 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454773 SCV000539713 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 family with prostate cancer and demonstrated "partial" segregation (not sure what that means, but other uses of this term in the paper included examples of nonsegregation, ie affected individuals who did not carry the variant); ClinVar: 1 VUS

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