ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.440G>A (p.Gly147Glu)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000781989 SCV000920445 likely pathogenic Lynch syndrome 2018-12-19 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability > 0.95 (0.966)
Invitae RCV000696093 SCV000824640 uncertain significance Hereditary nonpolyposis colon cancer 2018-03-12 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 147 of the MLH1 protein (p.Gly147Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine 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). 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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