ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.817G>A (p.Gly273Arg) (rs587779948)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212634 SCV000149352 uncertain significance not provided 2017-07-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.817G>A at the cDNA level, p.Gly273Arg (G273R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Gly273Arg was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Gly273Arg occurs at a position where amino acids with properties similar to Glycine are tolerated across species and is located in the nuclear localization signals (Gassman 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Gly273Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115443 SCV000215133 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-29 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000685169 SCV000812642 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 273 of the MSH6 protein (p.Gly273Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127605). 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, 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.
Color RCV000115443 SCV000904015 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-02 criteria provided, single submitter clinical testing

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