ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1742C>T (p.Pro581Leu)

gnomAD frequency: 0.00008  dbSNP: rs63751684
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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) RCV000075343 SCV000106337 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049. No CMMRD phenotype with co-occurrence & MAF 0.01-1%.
GeneDx RCV000034540 SCV000149375 likely benign not provided 2019-03-18 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 16425354, 26332594, 23526924, 26900293, 22703879, 22995991, 26078562, 20981092, 18069769, 21404117, 21155023, 23760103, 22949387, 24933000, 18094436, 27600092, 28445943, 29212164, 30740464, 31386297, 31784484)
Ambry Genetics RCV000115466 SCV000185318 benign Hereditary cancer-predisposing syndrome 2018-06-26 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001080084 SCV000218940 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-30 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000212543 SCV000539642 uncertain significance not specified 2016-03-28 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: Multiple papers in HGMD, isolated cases and some reference identification in control datasets; ExAC: 0.1% (12/8596) East Asian chromosomes
Color Diagnostics, LLC DBA Color Health RCV000115466 SCV000684768 likely benign Hereditary cancer-predisposing syndrome 2015-08-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212543 SCV000696125 likely benign not specified 2022-10-17 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1742C>T (p.Pro581Leu) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) 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 251256 control chromosomes, predominantly at a frequency of 0.0021 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1742C>T has been reported in the literature in individuals (mostly of East Asian origin) affected with Lynch Syndrome (e.g. Wang_2005, Hardt_2011, Hu_2013, Raskin_2017, Zhang_2017). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome, with contradictory reports of its presence in MSI-high, MLH1 IHC negative and MSS, MLH1 IHC positive tumors. One publication with functional data suggests that the variant could weaken MLH1-PMS2 binding (Fan_2007). However, Drost_2018 and Houlleberghs_2020 showed this variant as the same MMR activity as wild type and indicated as non-pathogenic effect. Co-occurrences with other pathogenic variants have been reported (ATM c.3284+1G>A in an internal sample, and PMS2 c.631C>T (p. Arg211*), MLH1 c.2252_2253dup (p. Val752Ly6sfs*32) in the InSiGHT database, where non-segregation for the variant of interest in 3 CRC affected individuals was also noted), providing supporting evidence for a benign role. Eight ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=5) and benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034540 SCV001134297 likely benign not provided 2019-05-06 criteria provided, single submitter clinical testing
Mendelics RCV000987183 SCV001136422 benign Colorectal cancer, hereditary nonpolyposis, type 2 2019-05-28 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000115466 SCV002528672 likely benign Hereditary cancer-predisposing syndrome 2021-05-18 criteria provided, single submitter curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212543 SCV004024910 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003934879 SCV004754091 likely benign MLH1-related disorder 2019-10-25 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Biesecker Lab/Clinical Genomics Section, National Institutes of Health RCV000034540 SCV000043325 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.

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