ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1820T>A (p.Leu607His) (rs41295284)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115467 SCV000183756 likely benign Hereditary cancer-predisposing syndrome 2017-08-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,Other data supporting benign classification
Color RCV000115467 SCV000684773 likely benign Hereditary cancer-predisposing syndrome 2015-02-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212544 SCV000592421 likely benign not specified 2014-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000212544 SCV000149376 likely benign not specified 2017-12-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Integrated Genetics/Laboratory Corporation of America RCV000212544 SCV000696128 likely benign not specified 2019-03-18 criteria provided, single submitter clinical testing MLH1 c.1820T>A (p.Leu607His) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 280238 control chromosomes (in gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00017 vs 0.00071), allowing no conclusion about variant significance. Although the population data are not clearly supportive for a benign outcome, it may still suggest that the variant could be a rare polymorphism. The variant of interest has been reported in individuals affected with Lynch Syndrome or Lynch-syndrome associated cancers, including a family showing lack of co-segregation (Perez-Cabornero 2013). The variant has been functionally assessed to have no effect on splicing (Tournier 2008, Borras 2012) and MMR activity (Takahashi 2007) although one study (Xie 2010) indicated that the variant affects FANCJ binding which could play a role in disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (5x likely benign, 2x VUS). Based on the evidence outlined above, the variant was classified as likely benign.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075372 SCV000106367 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV000524252 SCV000219095 likely benign Hereditary nonpolyposis colon cancer 2018-01-01 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212544 SCV000539635 likely benign not specified 2016-10-13 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant reported in 10 papers with functional data supporting non-pathogenic. Max MAF in ExAC is 0.04%. Classified by InSiGHT as Likely Benign (3 stars in ClinVar).
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000212544 SCV000691864 uncertain significance not specified no assertion criteria provided clinical testing
Mendelics RCV000075372 SCV000838024 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212544 SCV000601369 uncertain significance not specified 2017-05-17 criteria provided, single submitter clinical testing

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