ClinVar Miner

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

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Total submissions: 5
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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 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000195931 SCV000254297 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-25 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 2018-07-25 criteria provided, single submitter clinical testing

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