ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.244A>G (p.Thr82Ala) (rs587778998)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000506252 SCV000604231 likely pathogenic not specified 2016-12-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV000166056 SCV000216818 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 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),Well-characterized mutation at same position,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000166056 SCV000908603 likely pathogenic Hereditary cancer-predisposing syndrome 2018-07-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075602 SCV000592341 pathogenic Lynch syndrome 2013-01-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000075602 SCV000696155 likely pathogenic Lynch syndrome 2016-03-14 criteria provided, single submitter clinical testing Variant summary: This c.244A>G variant affects a conserved nucleotide, resulting in amino acid change from Thr to Ala. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 1/122056 control chromosomes from the broad and large populations of ExAC at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic allele (0.0007105) in this gene. This variant has been reported in multiple patients (at least five independent occurrences) affected with HNPCC or HNPCC-related cancers. There are no reported cosegregation studies for this variant. The variant has been functionally characterized to impair the MMR activity, strongly suggesting for pathogenic outcome. Multiple clinical laboratories as well as reputable databases have classified this variant as likely pathogenic. Multifactorial likelihood analysis for the variant is also in line with likely pathogenic outcome. Taken together this variant has currently been classfied as a Probable Disease Variant/Likely Pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490565 SCV000106599 likely pathogenic Lynch syndrome I 2018-06-13 reviewed by expert panel curation Variant reclassification due to new tumour Likelihood Ratios: Multifactorial likelihood analysis posterior probability > 0.95 (0.965)
Invitae RCV000542720 SCV000625139 pathogenic Hereditary nonpolyposis colon cancer 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 82 of the MLH1 protein (p.Thr82Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs587778998, ExAC 0.001%). This variant has been observed in several individuals affected with Lynch syndrome (PMID: 21239990, 21404117, 22736432, 26300997, 28514183). ClinVar contains an entry for this variant (Variation ID: 90116). Experimental studies have shown that this missense change significantly reduced DNA mismatch repair activity of MLH1 (PMID: 22736432). The p.Thr82 amino acid residue in MLH1 has been determined to be clinically significant (PMID: 10422993, 20587412, 19690142, 17510385, 23403630). This suggests that variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.

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