ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2960C>T (p.Thr987Ile) (rs587779928)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115397 SCV000149306 uncertain significance not provided 2018-07-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2960C>T at the cDNA level, p.Thr987Ile (T987I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr987Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr987Ile is located in the Clamp domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on the currently available information, we consider MSH6 Thr987Ile to be a variant of uncertain significance.
Ambry Genetics RCV000221869 SCV000275103 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000558179 SCV000624805 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-04 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 987 of the MSH6 protein (p.Thr987Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 127576). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000221869 SCV000690304 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-25 criteria provided, single submitter clinical testing
Counsyl RCV000662547 SCV000785129 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-05-08 criteria provided, single submitter clinical testing

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