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
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 RCV001201396 SCV000543660 likely pathogenic Hereditary nonpolyposis colon cancer 2019-10-30 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 (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) This variant has been reported to affect MLH1 protein function (PMID: 23403630, 18094436, 15475387). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000564174 SCV000676062 likely pathogenic Hereditary cancer-predisposing syndrome 2019-07-31 criteria provided, single submitter clinical testing 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;Rarity in general population databases (dbsnp, esp, 1000 genomes)

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