Submissions for variant NM_000249.4(MLH1):c.1964T>C (p.Ile655Thr)

gnomAD frequency: 0.00010  dbSNP: rs63751225

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128924	SCV000172794	likely benign	Hereditary cancer-predisposing syndrome	2018-10-29	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
GeneDx	RCV000034544	SCV000211118	likely benign	not provided	2019-09-11	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 17510385, 22703879, 8938136, 17348456, 10970186, 18383312, 16341804, 11376800, 25637381, 27600092, 31159747, 31332305)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085205	SCV000284039	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000662533	SCV000785103	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-18	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000128924	SCV000822021	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128924	SCV000910738	likely benign	Hereditary cancer-predisposing syndrome	2015-07-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781539	SCV000919656	likely benign	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1964T>C (p.Ile655Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251246 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.6e-05 vs 0.00071), allowing no conclusion about variant significance. c.1964T>C has been reported in the literature in individuals with a personal or family history of colorectal or other MLH1-related cancers, and at-least one instance of co-occurrence in a patient with hMLH1 promoter hypermethylation suggestive of a sporadic etiology has been ascertained (e.g., Irmejs_2007, Keller_1996, Potocnik_2001, Ravnik-Glavac_2000, Schubert_2019, Svensson_2022, Tsoaousis_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch syndrome. A co-occurrence with another pathogenic variant has been reported (MSH2 c.1786_1788del, p.Asn596del; Irmejs_2007), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 74% of normal activity in an in-vitro MMR assay and >75% relative MLH1 expression (Takahashi_2007). The following publications have been ascertained in the context of this evaluation (PMID: 31697235, 22290698, 25637381, 18383312, 11179758, 17348456, 22703879, 8938136, 27647783, 11376800, 10970186, 30426508, 35430768, 17510385, 31159747). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign, n = 6; VUS, n = 6). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034544	SCV001470332	uncertain significance	not provided	2024-10-10	criteria provided, single submitter	clinical testing	The MLH1 c.1964T>C (p.Ile655Thr) variant has been reported in the published literature in individuals with hereditary non-polyposis colon cancer (HNPCC), also known as Lynch syndrome (PMID: 11376800 (2001), 10970186 (2000), 8938136 (1996)), including one individual who also carried a pathogenic MSH2 variant (PMID: 17348456 (2007)). Additionally, this variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer, and at least one reportedly healthy individual (PMIDs: 33471991 (2021), 31159747 (2019), see also LOVD (https://databases.lovd.nl/shared)). Functional studies demonstrated that this variant was not damaging to protein function (PMID: 17510385 (2007)). The frequency of this variant in the general population, 0.00016 (4/25086 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034544	SCV002009369	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000781539	SCV002070339	uncertain significance	not specified	2020-08-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.1964T>C, in exon 17 that results in an amino acid change, p.Ile655Thr. This sequence change has been described in the gnomAD database with a low frequency of 0.016% in the European sub-population (dbSNP rs63751225). The p.Ile655Thr change affects a poorly conserved amino acid residue located in a domain of the MLH1 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ile655Thr substitution. The p.Ile655Thr change has previously been described in a family with gastric cancer (PMID: 8938136); however, functional studies have demonstrated mismatch repair activity similar to that of the wild type allele in the presence of this sequence change (PMID: 17510385). Due to these contrasting evidences, the clinical significance of the p.Ile655Thr change remains unknown at this time.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000781539	SCV002550465	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034544	SCV003916425	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	MLH1: BS3:Supporting
Myriad Genetics, Inc.	RCV000662533	SCV004018170	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2024-11-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
All of Us Research Program, National Institutes of Health	RCV004806018	SCV005427900	likely benign	Lynch syndrome	2024-09-17	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034544	SCV000043329	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000148623	SCV000190338	uncertain significance	Colorectal cancer, non-polyposis	2014-06-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003944879	SCV004773342	likely benign	MLH1-related disorder	2020-03-03	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).