ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3716T>C (p.Ile1239Thr) (rs786203816)

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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 RCV000167288 SCV000218131 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000478326 SCV000567233 uncertain significance not provided 2017-12-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3716T>C at the cDNA level, p.Ile1239Thr (I1239T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile1239Thr was not observed in large population cohorts (Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ile1239Thr is located in the ATPase 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 Ile1239Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000550915 SCV000624905 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-22 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 1239 of the MSH6 protein (p.Ile1239Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 187550). 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 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.
Color RCV000167288 SCV000690390 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-20 criteria provided, single submitter clinical testing

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