ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3600A>G (p.Ile1200Met) (rs587781482)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129441 SCV000184211 uncertain significance Hereditary cancer-predisposing syndrome 2016-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000412406 SCV000489165 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-29 criteria provided, single submitter clinical testing
GeneDx RCV000766608 SCV000567957 uncertain significance not provided 2018-12-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3600A>G at the cDNA level, p.Ile1200Met (I1200M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Ile1200Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the ATPase 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 Ile1200Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478382 SCV000601579 uncertain significance not specified 2017-05-24 criteria provided, single submitter clinical testing
Invitae RCV000539721 SCV000624888 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with methionine at codon 1200 of the MSH6 protein (p.Ile1200Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. This variant is present in population databases (rs587781482, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 141085). 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 C0"). 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.

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