ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2597A>C (p.Lys866Thr) (rs190075874)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222631 SCV000277588 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Insufficient evidence
Invitae RCV000524146 SCV000551133 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 866 of the MSH6 protein (p.Lys866Thr). The lysine residue is moderately conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs190075874, ExAC 0.03%). This variant has not been reported in the literature in individuals with an MSH6-related disease. It has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 89291). While algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this variant (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"), an algorithm developed specifically for the MSH6 gene (PMID: 23621914) suggests that this missense change may be deleterious. These predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000759136 SCV000568032 uncertain significance not provided 2017-02-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2597A>C at the cDNA level, p.Lys866Thr (K866T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Lys866Thr was observed with an allele frequency of 0.1% in the African populations in 1000 Genomes. Since Lysine and Threonine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Lys866Thr occurs at a position that is conserved across species and is located within the lever domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Lys866Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000479488 SCV000595853 uncertain significance not specified 2016-10-25 criteria provided, single submitter clinical testing
Counsyl RCV000662498 SCV000785020 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-03-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759136 SCV000888261 uncertain significance not provided 2017-10-13 criteria provided, single submitter clinical testing

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