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

gnomAD frequency: 0.00008  dbSNP: rs63751684

Total submissions: 13

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.
Labcorp Genetics (formerly Invitae), Labcorp	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
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.
PreventionGenetics, part of Exact Sciences	RCV003934879	SCV004754091	likely benign	MLH1-related disorder	2019-10-25	no assertion criteria provided	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).