ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.350C>T (p.Thr117Met) (rs63750781)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075666 SCV000106668 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Abrogated function, >2 MSI-H tumours, co-segregation with disease & MAF 0.00. Multifactorial likelihood analysis posterior probability >0.99
GeneDx RCV000160518 SCV000211084 pathogenic not provided 2018-06-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.350C>T at the cDNA level, p.Thr117Met (T117M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Several functional studies have shown that MLH1 Thr117Met does not have a dominant mutator effect (Shimodaira 1998, Shcherbakova 1999, Vogelsang 2009) and exhibits abrogated or significantly reduced MMR activity in vitro (Hinrichsen 2013, Trojan 2002, Plotz 2006), both of which are consistent with pathogenicity. This variant has been published in dozens of unrelated affected probands, of varying ethnicities, all meeting Amsterdam I or II criteria for Lynch syndrome, and has been reported to co-segregate with disease in multiple kindreds (Liu 1996, Maliaka 1996, Deiumegard 2000, Gille 2002, Wei 2003, InSiGHT). The vast majority of colon cancers tested in individuals with MLH1 Thr117Met exhibited microsatellite instability and/or loss of MLH1 protein expression on immunohistochemistry (Liu 1996, Dieumegard 2000, Gille 2002). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on their multifactorial likelihood analysis (Thompson 2014). MLH1 Thr117Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Methionine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Thr117Met occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is located in the ATPase domain (Andersen 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, we consider this variant to be pathogenic.
Invitae RCV000524293 SCV000211908 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 117 of the MLH1 protein (p.Thr117Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in many families and individuals with colon cancer and Lynch syndrome (PMID: 18566915, 22322191, 20233461, 15713769, 12112654, 19698169). ClinVar contains an entry for this variant (Variation ID: 17094). Multiple experimental studies have shown that this missense change results in an unstable protein with disrupted protein interactions and defective mismatch repair activity (PMID: 11781295, 17135187, 23403630, 12810663, 11429708, 17510385, 9697702). A multifactorial likelihood analysis incorporating genetic, clinical, and bioinformatic data (PMID: 19267393), and an algorithm developed specifically for the MLH1 gene (PMID: 18383312), indicate that this variant has a high probability of being pathogenic. In addition, multiple missense mutations have been reported in this region in individuals with colorectal cancer, suggesting that this is an important domain for MLH1 function (PMID: 17510385). For these reasons, this sequence change has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000075666 SCV000266078 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000075666 SCV000271399 pathogenic Lynch syndrome 2016-03-23 criteria provided, single submitter clinical testing The p.Thr117Met variant in MLH1 has been reported in >50 individuals with MLH1-a ssociated tumors (Kurzawski 2002, Wei 2003, Liu 1996, Maliaka 1996, Yap 2008, Ca sey 2005; InSiGHT database: http://chromium.lovd.nl/LOVD2/colon_cancer/variants. php) and segregated with disease in at least 2 affected family members (Zavodna 2006). This variant was absent from large population studies. In vitro functiona l studies provide some evidence that the p.Thr117Met variant is deficient in mis match repair (Trojan 2002). Computational prediction tools and conservation anal ysis suggest that this variant may impact the protein, though this information a lone is not predictive enough to determine pathogenicity. Additionally, this var iant has been classified as pathogenic on Nov 26, 2014 by the ClinGen-approved I nSiGHT panel (ClinVar SCV000211908.2). In summary, this variant meets our criter ia to be classified as pathogenic for Lynch syndrome in an autosomal dominant ma nner. ACMG/AMP criteria applied: PS4, PM2, PS3, PP3 (Richards 2015).
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075666 SCV000592354 pathogenic Lynch syndrome 2014-04-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000570680 SCV000669513 pathogenic Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Color RCV000570680 SCV000684820 pathogenic Hereditary cancer-predisposing syndrome 2020-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000075666 SCV000696163 pathogenic Lynch syndrome 2016-04-15 criteria provided, single submitter clinical testing Variant summary: The c.350C>T variant in MLH1 gene is a missense change that alters a highly conserved nucleotide and 4/4 in silico tools predict deleterious outcome. The variant has been reported in multiple affected individuals and was shown to segregate with the disease (Wei_CG_2003). IHC showed selective loss of the MLH1 protein in tumors from patients testing positive for the variant of interest and cells containing the T117M lost the ability to repair mismatched DNA both in vivo and in vitro (Takanashi, 2007; Hinrichsen, 2016). The variant is absent from the large control population dataset of ExAC. Lastly, a reputable database/diagnostic center classified the variant of interest as Pathogenic. Taken together, the variant was classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160518 SCV000888183 pathogenic not provided 2015-07-02 criteria provided, single submitter clinical testing
OMIM RCV000018626 SCV000038909 pathogenic Lynch syndrome II 2003-09-01 no assertion criteria provided literature only
Pathway Genomics RCV000144599 SCV000189926 pathogenic Lynch syndrome I 2014-07-24 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000160518 SCV000691846 pathogenic not provided no assertion criteria provided clinical testing
Ding PR Lab,Sun Yat-sen University Cancer Center RCV000144599 SCV001250869 likely pathogenic Lynch syndrome I no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249927 SCV001423869 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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