ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.976G>A (p.Val326Met) (rs730881739)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160530 SCV000211099 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.976G>A at the cDNA level, p.Val326Met (V326M) 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. MLH1 Val326Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Val326Met is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Val326Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000469188 SCV000543626 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with methionine at codon 326 of the MLH1 protein (p.Val326Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colon cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 182522). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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.
Ambry Genetics RCV000566682 SCV000662048 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000566682 SCV000684886 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing

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