ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2059C>T (p.Arg687Trp) (rs63751275)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215428 SCV000276415 pathogenic Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other data supporting pathogenic classification
Counsyl RCV000411954 SCV000488014 pathogenic Lynch syndrome II 2015-12-18 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763106 SCV000893648 likely pathogenic Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000481137 SCV000565167 pathogenic not provided 2018-11-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2059C>T at the cDNA level, p.Arg687Trp (R687W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed in multiple individuals with personal and/or family histories suggestive of Lynch syndrome, has been found to segregate with Lynch-related cancer diagnoses in several kindreds, and is considered a founder variant in the Swedish population (Jakubowska 2001, Caldes 2002, Furukawa 2002, Christensen 2009, Nilbert 2009, Zumstein 2016, von Salome 2017). In addition, this variant was identified in the homozygous state in three siblings with constitutional mismatch repair deficiency syndrome (Gallinger 2004, Durno 2012, Bakry 2014). Although Christensen et al. (2009) found normal protein expression and mismatch repair (MMR) activity comparable to wild-type, Takahashi et al. (2007) demonstrated that MLH1 Arg687Trp led to reduced mismatch repair activity, no dominant mutator effect, and reduced protein expression. Finally, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic based on their multifactorial likelihood analysis (Thompson 2014). MLH1 Arg687Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the PMS2/MLH3/PMS1 interaction region (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on current evidence, we consider MLH1 Arg687Trp to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000075499 SCV000696141 likely pathogenic Lynch syndrome 2017-05-16 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.2059C>T (p.Arg687Trp) variant involves a conserved nucleotide and results in replacement of a large size and basic Arginine (R) with a large size and aromatic Tryptophan (W) and is located in DNA mismatch repair protein Mlh1, C-terminal domain of the protein (InterPro). 4/4 in silico prediction tools predict disease-causing outcome for this change (SNPs&GO was not considered due to low reliability). This variant was found in 3/121776 control chromosomes at a frequency of 0.0000246, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). The MLH1 p.Arg687Trp missense mutation has been identified in several CRC families from different populations, e.g., Spain, Japan, Australia and Sweden (Arnold_HM_2009; Caldes_IJC_2002; Lagerstedt Robinson_J Natl Cancer Inst_2007; Furukawa_Cancer_2002). It has been reported to cosegregate with disease in multiple families, in two affected members from Australian family (Arnold_HM_2009), in three affected relatives from Spanish family (Caldes_2002) and in seven affected relatives over 3 generations in Danish family that met the Amsterdam criteria (Christensen_FC_2009). In addition, 3 children affected with gastrointestinal cancers and neurofibromatosis type 1 (CMMRD phenotype) carried this germline variant in homozygous state (Bakry_EJC_2014; Gallinger_GasreoE_2004). However, this variant did not segregate consistently with disease in two Swedish families (Lagerstedt Robinson_J Natl Cancer Inst_2007). In addition, in a family that did not meet Amsterdam-II criteria, a low LOD score of 1.5 was observed (Caldes_IJC_2002). At the functional level, MLH1 p.Arg687Trp demonstrated pathogenic phenotype in three functional assays in yeast (Takahashi_Cancer Res_2007). The same study also showed that MLH1 p.Arg687Trp exhibited reduced MMR activity and expression using a human cell-based system indicating a role in disease development. In contrast, study by Christensen_FC_2009 demonstrated that MLH1 p.Arg687Trp behaved as WT MLH1, both with regard to expression and MMR efficiency using a similar expression system. In addition, sub-cellular localization analysis demonstrated that the MLH1 p.Arg687Trp protein acted similar to WT MLH1. Multiple clinical laboratories/reputable databases in ClinVar have classified it as likely pathogenic/pathogenic. To summarize, while there are some conflicts on functional evidences regarding the variants effect on MLH1 function, the genetic evidence showing co-segregation with disease and very low allele frequency in general population strongly support that it is likely to have clinical significance. Therefore, this variant is currently classified as likely pathogenic.
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
Invitae RCV000524272 SCV000253681 pathogenic Hereditary nonpolyposis colon cancer 2018-09-12 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 687 of the MLH1 protein (p.Arg687Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs63751275, ExAC 0.01%). This variant has been reported in individuals and families affected with Lynch syndrome, constitutional mismatch repair deficiency syndrome, as well as colorectal and gastrointestinal cancer (PMID: 11139242, 11748856, 14762794, 19697156, 21404117, 24440087, 26485756). In several families, this variant co-segregated with disease (PMID: 11748856, 11920650, 19697156, 21404117). ClinVar contains an entry for this variant (Variation ID: 90014). An experimental study has shown that this variant affects mismatch repair activity in yeast-based functional assays, and MLH1 protein expression in vitro (PMID: 17510385). However, another study has shown that this variant has comparable protein stability, mismatch repair efficiency, and subcellular localization to wild-type (PMID: 19697156) For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481137 SCV000601383 likely pathogenic not provided 2016-11-01 criteria provided, single submitter clinical testing

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