ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.806C>T (p.Thr269Ile) (rs587779322)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482210 SCV000571831 uncertain significance not provided 2016-09-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.806C>T at the cDNA level, p.Thr269Ile (T269I) 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 Thr269Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr269Ile occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Thr269Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000569264 SCV000662455 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Invitae RCV000807648 SCV000947713 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 269 of the MSH6 protein (p.Thr269Ile). 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: 422371). 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 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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