ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1820T>A (p.Leu607His) (rs41295284)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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
GeneDx RCV001703975 SCV000149376 likely benign not provided 2020-11-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19389263, 17510385, 18561205, 20978114, 10713887, 11839723, 21681552, 23523604, 22949387, 18566915, 23588873, 22736432, 21056691, 18033691, 15365995, 11369138, 25871441, 20978117, 26637282, 23741719, 17192056, 24933000, 15222003, 26926912, 31784484)
Ambry Genetics RCV000115467 SCV000183756 likely benign Hereditary cancer-predisposing syndrome 2018-09-07 criteria provided, single submitter clinical testing Other data supporting benign classification
Invitae RCV000524252 SCV000219095 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 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).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000212544 SCV000592421 likely benign not specified 2014-12-18 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
Color Health, Inc RCV000115467 SCV000684773 likely benign Hereditary cancer-predisposing syndrome 2015-02-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212544 SCV000696128 likely benign not specified 2020-09-23 criteria provided, single submitter clinical testing Variant summary: 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 0.00018 in 254496 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (0.00018 vs 0.00071), allowing no conclusion about variant significance. Although the control population data is not clearly supportive for a benign outcome, it may still suggest that the variant could be a rare polymorphism. c.1820T>A has been reported in the literature in individuals affected with Lynch Syndrome or Lynch-syndrome associated cancers (e.g. Fidalgo_2000, Cravo_2002, Barnetson_2008, Valentin_2011, Castillejo_2014 ), including a family showing lack of co-segregation (Perez-Cabornero 2013). The variant has been functionally characterized and shown to have no effect on splicing (Tournier 2008, Borras 2012) and MMR activity (Takahashi 2007, Houlleberghs_2020) although one study (Xie 2010) indicated that the variant affects FANCJ binding which could play a role in disease. Seven ClinVar submitters (evaluation after 2014) cite the variant as likely benign while two ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000075372 SCV000838024 likely benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000987185 SCV001136424 likely benign Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000987185 SCV001305809 uncertain significance Lynch syndrome II 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Mayo Clinic Laboratories, Mayo Clinic RCV000212544 SCV000691864 uncertain significance not specified no assertion criteria provided clinical testing

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