ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3485C>A (p.Ala1162Asp) (rs587779935)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212684 SCV000149325 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3485C>A at the cDNA level, p.Ala1162Asp (A1162D) at the protein level, and results in the change of an Alanine to an Aspartic Acid (GCT>GAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala1162Asp was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ala1162Asp occurs at a position that is conserved across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). 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 Ala1162Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115416 SCV000212821 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000819197 SCV000959844 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 1162 of the MSH6 protein (p.Ala1162Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 127587). 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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