ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3703C>G (p.Leu1235Val) (rs876661084)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000218152 SCV000279484 uncertain significance not provided 2017-12-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3703C>G at the cDNA level, p.Leu1235Val (L1235V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Leu1235Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1235Val is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Leu1235Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000570599 SCV000662581 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000570599 SCV000685431 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
Invitae RCV000630095 SCV000751051 uncertain significance Hereditary nonpolyposis colon cancer 2017-10-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1235 of the MSH6 protein (p.Leu1235Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234558). 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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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