ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.221A>T (p.Asp74Val) (rs751894165)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000460878 SCV000543579 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 74 of the MLH1 protein (p.Asp74Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs751894165, ExAC 0.001%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 405401). 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: "Benign"; Align-GVGD: "Class C0"). In summary, this variant has uncertain impact on MLH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000522233 SCV000617961 uncertain significance not provided 2018-09-07 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.221A>T at the cDNA level, p.Asp74Val (D74V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Asp74Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Asp74Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000774691 SCV000908602 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing

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