ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3257C>T (p.Pro1086Leu) (rs780345806)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000222192 SCV000279488 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3257C>T at the cDNA level, p.Pro1086Leu (P1086L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant was observed in an individual with a personal history of a Lynch syndrome associated cancer or polyps (Yurgelun 2015). MSH6 Pro1086Leu was not observed in large population cohorts (Lek 2016). This variant is located in the ATPase 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 Pro1086Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000536806 SCV000624838 uncertain significance Hereditary nonpolyposis colon cancer 2018-09-17 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1086 of the MSH6 protein (p.Pro1086Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 234562). 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 leucine 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.
Ambry Genetics RCV000562792 SCV000673930 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-19 criteria provided, single submitter clinical testing Insufficient evidence

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