ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1915G>A (p.Glu639Lys) (rs143517321)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164891 SCV000215577 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524126 SCV000254285 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 639 of the MSH6 protein (p.Glu639Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs143517321, ExAC 0.003%). This variant has been reported in individuals affected with colon cancer and glioma (PMID: 27978560, 26845104, 26689913). ClinVar contains an entry for this variant (Variation ID: 185463). Algorithms developed to predict the effect of missense changes on protein structure and function of do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). However, an algorithm developed specifically for the MSH6 gene (PMID: 23621914) suggests that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies and its 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000200231 SCV000266204 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001094683 SCV000430966 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000480270 SCV000566008 uncertain significance not provided 2018-02-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1915G>A at the cDNA level, p.Glu639Lys (E639K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been observed in at least two individuals with colorectal cancer and in one individual with glioma (Lu 2015, Shirts 2016, Pearlman 2017). MSH6 Glu639Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the connector 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 Glu639Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164891 SCV000685239 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-17 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000480270 SCV000805852 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480270 SCV000889468 uncertain significance not provided 2018-08-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781602 SCV000919774 uncertain significance not specified 2018-11-13 criteria provided, single submitter clinical testing Variant summary: MSH6 c.1915G>A (p.Glu639Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276788 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1915G>A has been reported in the literature in individuals affected with colon cancer and glioma. These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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