ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2108T>C (p.Met703Thr) (rs1064793189)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000486361 SCV000565223 uncertain significance not provided 2016-04-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2108T>C at the cDNA level, p.Met703Thr (M703T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Met703Thr 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 Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Met703Thr occurs at a position that is not conserved and is located within domain II of the MutS domain (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Met703Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563641 SCV000669918 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000703273 SCV000832168 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 703 of the MSH6 protein (p.Met703Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 418326). 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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