ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.956C>T (p.Thr319Met) (rs188252826)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168389 SCV000219082 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 319 of the MSH6 protein (p.Thr319Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is present in population databases (rs188252826, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 188357). 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.
Ambry Genetics RCV000220509 SCV000273992 likely benign Hereditary cancer-predisposing syndrome 2018-10-31 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508128 SCV000601623 uncertain significance not specified 2017-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000656996 SCV000616946 uncertain significance not provided 2017-12-04 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.956C>T at the cDNA level, p.Thr319Met (T319M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr319Met was not observed in large population cohorts (Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr319Met is located within the nuclear localization signals (Gassman 2011). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Thr319Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000220509 SCV000903540 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing

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