ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3111C>G (p.Phe1037Leu) (rs587781673)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160689 SCV000211310 uncertain significance not provided 2018-01-08 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3111C>G at the cDNA level, p.Phe1037Leu (F1037L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTC>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Phe1037Leu 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 a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Phe1037Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564450 SCV000669998 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-03 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000564450 SCV000685353 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000691133 SCV000818876 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-08-28 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 1037 of the MSH6 protein (p.Phe1037Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is present in population databases (rs587781673, ExAC 0.01%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 182642). 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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