ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2693C>G (p.Pro898Arg) (rs876661281)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588498 SCV000279981 uncertain significance not provided 2018-12-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2693C>G at the cDNA level, p.Pro898Arg (P898R) at the protein level, and results in the change of a Proline to an Arginine (CCT>CGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Pro898Arg was not observed in large population cohorts (Lek 2016). MSH6 Pro898Arg is located in the lever domain (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 Pro898Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000530480 SCV000624785 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces proline with arginine at codon 898 of the MSH6 protein (p.Pro898Arg). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000563804 SCV000664734 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000588498 SCV000695822 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The c.2693C>G (p.Pro898Arg) in MSH6 gene is a missense change that involves a highly conserved nucleotide and 3/4 in silico tools predict deleterious outcome. The variant is located within the MutS domain III domain and mutations in this domain have been reported as causal in LS pts. The variant of interest was not observed in control datasets of ExAC and gnomAD (120586 and 245446 chrs tested, respectively). The c.2693C>G has not, to our knowledge, been reported in affected individuals via published reports, but is listed as VUS by a reputable database/clinical laboratory without evidence to independently evaluate. Taking together, the variant was classified as VUS.
Mendelics RCV000708880 SCV000837902 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing

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