ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.194G>A (p.Gly65Asp) (rs63751465)

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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 RCV000564174 SCV000676062 likely pathogenic Hereditary cancer-predisposing syndrome 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Structural Evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075435 SCV000106431 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV000075435 SCV000543660 uncertain significance Lynch syndrome 2016-06-27 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 65 of the MLH1 protein (p.Gly65Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (rs63751465, ExAC no frequency). This variant has been reported in individuals affected with colorectal cancer (PMID: 14514376, 18094436), and an individual affected with breast cancer (PMID: 25927356) Experimental studies have shown that this variant causes a reduction in MLH1 protein expression and repair activity similar to other, known pathogenic MLH1 variants (PMID: 23403630, 18094436, 15475387). In summary, this variant is a rare missense change that has been reported to affect protein function, and has been reported in affected individuals. However, the available evidence is currently insufficient to determine its role in disease and in the absence of additional genetic and/or functional data, it has been classified as a Variant of Uncertain Significance.

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