ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2776C>T (p.Leu926Phe) (rs587781318)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129055 SCV000183753 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000212670 SCV000211302 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2776C>T at the cDNA level, p.Leu926Phe (L926F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Leu926Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Leu926Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000205831 SCV000261599 uncertain significance Hereditary nonpolyposis colon cancer 2017-06-09 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 926 of the MSH6 protein (p.Leu926Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 140848). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MSH6 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212670 SCV000889475 uncertain significance not provided 2018-03-26 criteria provided, single submitter clinical testing

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