ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2941A>G (p.Ile981Val) (rs730881799)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160684 SCV000211305 uncertain significance not provided 2015-12-21 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2941A>G at the cDNA level, p.Ile981Val (I981V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ile981Val 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 Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ile981Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the MutS domain IV (Terui 2013). 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 Ile981Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469541 SCV000551235 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-09 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 981 of the MSH6 protein (p.Ile981Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals affected with Lynch syndrome from a single family (PMID: 28481244). ClinVar contains an entry for this variant (Variation ID: 182638). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000565911 SCV000673922 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000565911 SCV000904023 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing

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