ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1742C>T (p.Pro581Leu) (rs63751684)

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Total submissions: 11
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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 Does not segregate with disease in family study (genes with complete penetrance);General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Invitae RCV001080084 SCV000218940 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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 Health, Inc 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 2019-07-30 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 Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, 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. At least one publication with functional data suggests that the variant could weaken MLH1-PMS2 binding (Fan_2007), however it has yet to confirmed by independent studies. 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. Five ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as uncertain significance (1x) and likely benign (4x). 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 Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034540 SCV001748065 likely benign not provided 2021-05-01 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.

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