ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1231A>T (p.Arg411Trp) (rs202219685)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000485452 SCV000567856 uncertain significance not provided 2015-09-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1231A>T at the cDNA level, p.Arg411Trp (R411W) at the protein level, and results in the change of an Arginine to a Tryptophan (AGG>TGG). This variant was observed in at least one patient with early onset breast cancer (Maxwell 2015). MSH6 Arg411Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg411Trp occurs at a position that is conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Arg411Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000563473 SCV000662428 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000629980 SCV000750936 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 411 of the MSH6 protein (p.Arg411Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with early-onset breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 419791). 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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