ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.503C>G (p.Ala168Gly) (rs774162322)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164360 SCV000214994 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000230583 SCV000283846 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 168 of the MSH6 protein (p.Ala168Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs774162322, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 185008). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000657018 SCV000566405 uncertain significance not provided 2018-04-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.503C>G at the cDNA level, p.Ala168Gly (A168G) at the protein level, and results in the change of an Alanine to a Glycine (GCA>GGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala168Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Ala168Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485808 SCV000601609 uncertain significance not specified 2017-06-29 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000485808 SCV000712660 uncertain significance not specified 2016-11-17 criteria provided, single submitter clinical testing The p.Ala168Gly variant in MSH6 has not been previously reported in individuals with hereditary cancer or in large population studies, but has been identified i n 1/66324 European chromosomes by the Exome Aggregation Consortium (ExAC, http:/ /; dbSNP rs774162322). Computational prediction tools and conservation analysis suggest that the p.Ala168Gly variant may not impact the p rotein with several species (fish) carrying the variant amino acid, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significance of the p.Ala168Gly variant is uncertain.
Counsyl RCV000662903 SCV000785824 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-12-12 criteria provided, single submitter clinical testing
Color RCV000164360 SCV000911011 likely benign Hereditary cancer-predisposing syndrome 2016-03-17 criteria provided, single submitter clinical testing

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