ClinVar Miner

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

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Total submissions: 9
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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
Invitae RCV000524272 SCV000253681 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-16 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.
Ambry Genetics RCV000215428 SCV000276415 pathogenic Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing 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
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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481137 SCV000601383 pathogenic not provided 2018-10-26 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in many symptomatic patients. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Results on protein functions were conflicting/inconclusive. Very strong co-segregation with disease.
Integrated Genetics/Laboratory Corporation of America 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 Turcot syndrome; Muir-Torré syndrome; Lynch syndrome II 2018-10-31 criteria provided, single submitter clinical testing
Ding PR Lab,Sun Yat-sen University Cancer Center RCV001093679 SCV001250860 uncertain significance Lynch syndrome I no assertion criteria provided clinical testing

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