ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2511C>G (p.His837Gln) (rs587779925)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212667 SCV000149301 uncertain significance not provided 2018-07-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2511C>G at the cDNA level, p.His837Gln (H837Q) at the protein level, and results in the change of a Histidine to a Glutamine (CAC>CAG). This variant has been reported in at least one woman with a personal history of breast cancer (Tung 2015). MSH6 His837Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 His837Gln 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 His837Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115392 SCV000184768 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000195931 SCV000254297 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with glutamine at codon 837 of the MSH6 protein (p.His837Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. This variant is present in population databases (rs587779925, ExAC 0.01%). This variant has been observed in an individual affected with colon cancer (Invitae). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.2511C>G variant was not the primary cause of disease. Additionally, this variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 127572). 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.
Counsyl RCV000412127 SCV000488057 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-18 criteria provided, single submitter clinical testing
Color RCV000115392 SCV000904019 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193702 SCV001362736 uncertain significance not specified 2019-11-26 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2511C>G (p.His837Gln) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 248300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2511C>G has been reported in the literature in at least one individual affected with hereditary breast cancer (Tung_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with another pathogenic variant has been reported (MLH1 c.1381A>T, p.K461X; internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other 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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