ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1025C>T (p.Ala342Val) (rs753617680)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481708 SCV000565857 uncertain significance not provided 2017-01-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1025C>T at the cDNA level, p.Ala342Val (A342V) at the protein level, and results in the change of an Alanine to a Valine (GCC>GTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Ala342Val 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 Alanine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Ala342Val occurs at a position where amino acids with properties similar to Alanine are tolerated across species and is located within the binding site of MSH2 (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 Ala342Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564150 SCV000669958 uncertain significance Hereditary cancer-predisposing syndrome 2017-01-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000564150 SCV000690164 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing
Invitae RCV000697119 SCV000825713 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-30 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 342 of the MSH6 protein (p.Ala342Val). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs753617680, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 418643). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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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