ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.25A>G (p.Ser9Gly) (rs41294986)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130571 SCV000185443 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000235178 SCV000211334 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.25A>G at the cDNA level, p.Ser9Gly (S9G) at the protein level, and results in the change of a Serine to a Glycine (AGC>GGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ser9Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ser9Gly 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 Ser9Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130571 SCV000537613 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing
Invitae RCV000475467 SCV000551236 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 9 of the MSH6 protein (p.Ser9Gly). The serine residue is moderately conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs41294986, ExAC 0.003%). This variant has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141874). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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.

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