ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.910G>A (p.Val304Met) (rs876661207)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000220303 SCV000279791 uncertain significance not provided 2016-01-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.910G>A at the cDNA level, p.Val304Met (V304M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Val304Met was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MSH6 Val304Met occurs at a position that is not conserved and is not located in a known functional domain (Kariola 2002, Terui 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Val304Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000540281 SCV000625020 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 304 of the MSH6 protein (p.Val304Met). The valine residue is weakly conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 234768). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect 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.
Counsyl RCV000663285 SCV000786527 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-05-21 criteria provided, single submitter clinical testing
Color RCV000771395 SCV000903734 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000220303 SCV001134462 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771395 SCV001180165 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-19 criteria provided, single submitter clinical testing Insufficient evidence

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