ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3713C>G (p.Thr1238Ser) (rs755349360)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164691 SCV000215358 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000458549 SCV000551205 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-22 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 1238 of the MSH6 protein (p.Thr1238Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs755349360, ExAC 0.02%) but has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 185296). 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. In summary, this variant is a rare missense change that is not predicted to affect 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.
GeneDx RCV000485750 SCV000565234 uncertain significance not provided 2018-07-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3713C>G at the cDNA level, p.Thr1238Ser (T1238S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Thr1238Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Kansikas 2011). 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 Thr1238Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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