Submissions for variant NM_000249.4(MLH1):c.2059C>T (p.Arg687Trp)

gnomAD frequency: 0.00001  dbSNP: rs63751275

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075499	SCV000106495	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524272	SCV000253681	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2025-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 687 of the MLH1 protein (p.Arg687Trp). This variant is present in population databases (rs63751275, gnomAD 0.01%). This missense change has been observed in individuals with Lynch syndrome, constitutional mismatch repair deficiency syndrome, as well as colorectal and gastrointestinal cancer (PMID: 11139242, 11748856, 11920650, 14762794, 19697156, 21404117, 24440087, 26485756). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 90014). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 16395668, 17510385). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000215428	SCV000276415	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-21	criteria provided, single submitter	clinical testing	The p.R687W pathogenic mutation (also known as c.2059C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2059. The arginine at codon 687 is replaced by tryptophan, an amino acid with dissimilar properties. This mutation has been reported in the heterozygous state in multiple families with Lynch syndrome (Jakubowska A et al. Hum Mutat, 2001;17:52-60; Godino J et al. Hum. Mutat., 2001 Dec;18:549;Furukawa T et al. Cancer, 2002 Feb;94:911-20; Caldes T et al. Int J Cancer, 2002 Apr;98:774-9; Kurzawski G et al. J Med Genet, 2002 Oct;39:E65; Lagerstedt Robinson K et al. J Natl Cancer Inst, 2007 Feb;99:291-9; Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83; (Hardt K et al. Fam Cancer, 2011 Jun;10:273-84; Zumstein V et al. Swiss Med Wkly, 2016 May;146:w14315; von Salomé J et al. Fam Cancer, 2017 Dec). One study reported segregation with disease in a large kindred (LOD score 1.5), including multiple individuals diagnosed with colon and/or endometrial cancer (Christensen LL et al. Fam Cancer, 2009 Aug;8:489-500). This mutation has also been observed in the homozygous state in multiple individuals from unrelated families with constitutional mismatch repair deficiency (CMMRD) syndrome (Gallinger S et al. Gastroenterology, 2004 Feb;126:576-85; Bakry D et al. Eur. J. Cancer, 2014 Mar;50:987-96). In one functional study, this mutation demonstrated lack of a dominant mutator effect (DME) and reduced MLH1 protein expression in yeast assays (Takahashi M et al. Cancer Res, 2007 May;67:4595-604). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Counsyl	RCV000411954	SCV000488014	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2015-12-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000481137	SCV000565167	pathogenic	not provided	2024-07-19	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18383312, 22949379, 23760103, 16042583, 24362816, 16395668, 15845562, 27629256, 18709565, 31830689, 29922827, 17510385, 21120944, 22736432, 22949387, 25525159, 11139242, 17192056, 15289847, 24440087, 22180144, 14762794, 11748856, 11920458, 11920650, 12362047, 16451135, 17312306, 18566915, 22120844, 21404117, 19267393, 27300758, 27152634, 27831900, 28874130, 29288294, 27601186, 25430799, 22290698, 16288214, 30521064, 30720243, 30787465, 33087929, 26485756, 34873480, 12799449, 20533529, 22753075, 19697156, 31391288, 35430768)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481137	SCV000601383	pathogenic	not provided	2024-05-13	criteria provided, single submitter	clinical testing	The MLH1 c.2059C>T (p.Arg687Trp) variant has been reported in the published literature in multiple individuals and families with Lynch syndrome, including as a founder mutation in the Swedish population (PMID: 29288294 (2018), 28874130 (2017), 27152634 (2016), 26485756 (2015), 21404117 (2011), 19697156 (2009), 17312306 (2007), 11920650 (2002), 11920458 (2002), 12362047 (2002), 11139242 (2001)). It has also been reported as homozygous in three siblings with constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 14762794 (2004)). Functional evidence for this variant is inconclusive since one experimental study showed that this variant reduced in-vitro MMR activity and MLH1 expression (PMID: 17510385(2007)) and another study showed that this variant was comparable to the wildtype MLH1 in its expression and MMR efficiency (PMID: 19697156 (2009)). The variant was shown to segregate with disease in multiple families (PMID: 19267393 (2009), 19697156 (2009), 14762794 (2004), 11920650 (2002)). The frequency of this variant in the general population, 0.000098 (3/30612 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 predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000075499	SCV000696141	pathogenic	Lynch syndrome	2019-04-23	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2059C>T (p.Arg687Trp) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal (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 2e-05 in 251916 control chromosomes (gnomAD). It has also has been reported in the literature in multiple individuals and families affected with Lynch syndrome, constitutional mismatch repair deficiency syndrome, colorectal and gastrointestinal cancers from different populations (e.g. Arnold_2009, Caldes_2002; Lagerstedt Robinson_2007; Furukawa_2002, Bakry_2014, Gallinger_2004). The variant co-segregated with the disease in multiple families (e.g. Arnold_2009, Caldes_2002, Christensen_2009) but not in all (Lagerstedt Robinson_2007). In addition, International Society for Gastrointestianl Heriditary Tumors (InSiGHT) and others have performed systematic investigation and classified this variant as pathogenic (Tricarico_2017). These data indicate that the variant is very likely to be associated with disease. One experimental study demonstrated that this variant affects function in yeast functional assays and reduce in vitro MMR activity and MLH1 expression (Takahashi_2007). In contrast Christensen et al (Christensen_2009) has shown that this variant behaved like WT-MLH1 in its expression, MMR efficiency and subcellular localization. Six submitters have provided clinical significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. They classified the variant as pathogenic (4x) /likely pathogenic (2x). Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763106	SCV000893648	likely pathogenic	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000481137	SCV001449572	pathogenic	not provided	2014-09-12	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000481137	SCV002017492	pathogenic	not provided	2022-08-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000215428	SCV002051835	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 687 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant resulted in functional DNA repair in vitro and normal protein stability (PMID: 17510385, 19697156). This variant has been reported in individuals affected with Lynch syndrome (PMID: 11748856, 11920458, 18566915, 19267393, 19697156, 21404117, 25430799, 27629256, 28874130, 29288294), CMMRD (24440087), colorectal cancer (PMID: 26485756, 27152634), or ovarian cancer (PMID: 19697156). This variant has been identified in 5/251196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Human Genetics Bochum, Ruhr University Bochum	RCV000411954	SCV002758588	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2022-06-18	criteria provided, single submitter	clinical testing	ACMG criteria used to clasify this variant: PM1, PM2, PP3, PP2, PP1
Myriad Genetics, Inc.	RCV000411954	SCV004018181	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2024-12-02	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11920650, 14762794]. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 27363726].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000411954	SCV004031248	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-26	criteria provided, single submitter	clinical testing	The MLH1 c.2059C>T (p.Arg687Trp) missense change has a maximum subpopulation frequency of 0.0098% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, and a functional study in yeast demonstrated a reduction in MMR activity and MLH1 protein expression (PMID: 17510385). This variant has been reported as heterozygous in individuals with a personal and/or family history of Lynch syndrome (PMID: 11139242, 11748856, 11920458, 11920650, 12362047, 17312306, 18566915, 19697156, 27152634, 29288294). It has also been reported as homozygous in multiple unrelated individuals with constitutional mismatch repair deficiency (PMID: 14762794, 24440087). In summary, this variant meets criteria to be classified as pathogenic.
Neuberg Centre For Genomic Medicine, NCGM	RCV000411954	SCV004047667	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2		criteria provided, single submitter	clinical testing	The c.2059C>T (p.Arg687Trp) missense variant has been reported in in individuals and families affected with Lynch syndrome, constitutional mismatch repair deficiency syndrome, as well as colorectal and gastrointestinal cancer (Jakubowska et al., 2001; Godino et al., 2001). In several families, this variant cosegregated with disease (Godino et al., 2001). An experimental study has shown that this variant affects mismatch repair activity in yeast-based functional assays, and MLH1 protein expression in vitro (Takahashi et al., 2007). This variant is reported with the allele frequency (0.001%) in the gnomAD and novel in 1000 genome database. It has been submitted to ClinVar as a Pathogenic variant. The amino acid Arg at position 687 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg687Trp in MLH1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV000411954	SCV004193016	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000075499	SCV004848306	pathogenic	Lynch syndrome	2019-10-14	criteria provided, single submitter	clinical testing	The p.Arg687Trp variant in MLH1 has been previously reported in at least 16 individuals with Lynch syndrome (von Salome 2018, Jakubowska 2001, Furukawa 2002, Caldes 2002) and 3 homozygous siblings affected with constitutive mismatch repair deficiency (Durno 2012). It is considered a founder mutation for Lynch syndrome in Sweden (von Salome 2018). It has also been identified in 3/30612 of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic by several clinical labs in ClinVar and on September 5, 2013 by the ClinGen-approved InSiGHT expert panel (Variation ID 90014). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro functional studies provide some evidence that this variant mildly impacts protein function (Takahashi 2007, Christensen 2009, Kansikas 2011); however, these types of assays may not accurately represent biological function. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP criteria applied: PS4, PP1_Strong, PM3, PM2_Supporting, PP4.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000481137	SCV005199152	pathogenic	not provided	2022-10-24	criteria provided, single submitter	clinical testing
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093679	SCV001250860	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356525	SCV001551724	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Arg687Trp variant was identified in 15 of 7816 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome and constitutional biallelic mismatch repair deficiency syndrome, and was not identified in 3420 control chromosomes from healthy individuals (Lagerstedt-Robinson 2016, von Salome 2017, Zumstein 2016, Bakry 2014, Caldes 2002, Gallinger 2004). The variant was also identified in the following databases: dbSNP (ID: rs63751275) as "With Pathogenic, Uncertain significance allele", ClinVar (4x likely pathogenic, 3x pathogenic including review by expert panel InSiGHT), Clinvitae, Cosmic (1x, confirmed somatic, in carcinoma of the large intestine), UMD-LSDB (6x, unclassified variant), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (58x, pathogenic). The variant was not identified in GeneInsight-COGR, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 5 of 245948 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15302 chromosomes (freq: 0.00007), European in 1 of 111454 chromosomes (freq: 0.000009), and South Asian in 3 of 30778 chromosomes (freq: 0.0001). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. Functional studies show conflicting results; a study by Christensen 2009 found protein expression, repair efficiency, and subcellular localization of the variant protein similar to wildtype MLH1. However, a study by Takahashi 2007 demonstrated a pathogenic phenotype in three functional assays in yeast, as well as reduced protein expression and mismatch repair activity. No effect in splicing was found in a cDNA splicing assay (Borras 2012). This variant has been found in a homozygous state in children diagnosed with constitutional biallelic mismatch repair deficiency syndrome (Gallinger 2004, Bakry 2014). In several families, this variant co-segregated with disease (Caldes 2002, Christensen 2009, Zumstein 2016). Although the p.Arg687 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Arg687Trp variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000481137	SCV001953270	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000481137	SCV001964249	likely pathogenic	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915039	SCV004728153	pathogenic	MLH1-related disorder	2024-01-16	no assertion criteria provided	clinical testing	The MLH1 c.2059C>T variant is predicted to result in the amino acid substitution p.Arg687Trp. This variant is considered to be a founder variant in the Swedish population and has been reported in individuals with hereditary non-polyposis colorectal cancer (Jakubowska et al. 2001. PubMed ID: 11139242), mismatch repair deficiency syndromes (Bakry et al. 2014. PubMed ID: 24440087), and Lynch syndrome (von Salomé et al. 2018. PubMed ID: 29288294). Functional studies have been discrepant regarding the impact of this variant on MLH1 function with reports ranging from wild type activity (Christensen et al. 2009. PubMed ID: 19697156) to reduced expression and MMR activity (Takahashi et al. 2007. PubMed ID: 17510385). This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD and has been interpreted as pathogenic by an expert review panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/90014). This variant is interpreted as pathogenic.