chr3-37047529-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP3BP4_ModerateBP6_Very_StrongBS1
The NM_000249.4(MLH1):c.1742C>T(p.Pro581Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P581S) has been classified as Likely benign.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000112 AC: 17AN: 152168Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000179 AC: 45AN: 251256Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135782
GnomAD4 exome AF: 0.0000581 AC: 85AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42AN XY: 727224
GnomAD4 genome AF: 0.000112 AC: 17AN: 152286Hom.: 0 Cov.: 31 AF XY: 0.000148 AC XY: 11AN XY: 74460
ClinVar
Submissions by phenotype
not specified Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | 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 - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Mar 04, 2025 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2022 | 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. - |
not provided Uncertain:1Benign:2
Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 18, 2019 | 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) - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 06, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 04, 2015 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 18, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2018 | 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. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Lynch syndrome Benign:1
Likely benign, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability 0.001-0.049. No CMMRD phenotype with co-occurrence & MAF 0.01-1%. - |
MLH1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 25, 2019 | 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). - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2025 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at