ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.977T>A (p.Val326Glu) (rs63751049)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219781 SCV000275924 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-22 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting pathogenic classification
Color RCV000219781 SCV001359185 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-14 criteria provided, single submitter clinical testing
Invitae RCV001232535 SCV001405097 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-31 criteria provided, single submitter clinical testing This sequence change replaces valine with glutamic acid at codon 326 of the MLH1 protein (p.Val326Glu). The valine residue is moderately conserved and there is a moderate physicochemical difference between valine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 231925). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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