ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1561A>T (p.Thr521Ser) (rs587779916)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115377 SCV000149286 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1561A>T at the cDNA level, p.Thr521Ser (T521S) at the protein level, and results in the change of a Threonine to a Serine (ACA>TCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Thr521Ser was not observed in large population cohorts (Lek 2016). This variant is located in Connector 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 Thr521Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000216113 SCV000273052 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000473285 SCV000551253 uncertain significance Hereditary nonpolyposis colon cancer 2017-12-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 521 of the MSH6 protein (p.Thr521Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127560). 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. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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