ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3565A>G (p.Thr1189Ala) (rs753778809)

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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 RCV000218856 SCV000275546 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000482279 SCV000571476 uncertain significance not provided 2018-05-10 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3565A>G at the cDNA level, p.Thr1189Ala (T1189A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Thr1189Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant 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 Thr1189Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000558107 SCV000624884 uncertain significance Hereditary nonpolyposis colon cancer 2018-01-16 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1189 of the MSH6 protein (p.Thr1189Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs753778809, 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: 231639). 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.

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