ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2107A>G (p.Met703Val) (rs751867550)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227011 SCV000283742 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-13 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 703 of the MSH6 protein (p.Met703Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs751867550, ExAC 0.003%) but has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 237151). 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, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000483631 SCV000565222 uncertain significance not provided 2018-05-20 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2107A>G at the cDNA level, p.Met703Val (M703V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Met703Val was not observed at a significant frequency in large population cohorts (Lek 2016). MSH6 Met703Val is located in 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 Met703Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000580465 SCV000685257 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-07 criteria provided, single submitter clinical testing
Counsyl RCV000662419 SCV000784855 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-01-11 criteria provided, single submitter clinical testing
Mendelics RCV000708872 SCV000837892 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000662419 SCV001135815 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580465 SCV001175163 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-06 criteria provided, single submitter clinical testing Insufficient evidence

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