ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2246T>C (p.Leu749Pro) (rs267607894)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216146 SCV000278167 pathogenic Hereditary cancer-predisposing syndrome 2017-11-07 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,Other data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
Color RCV000216146 SCV000905472 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing
GeneDx RCV000478074 SCV000565172 pathogenic not provided 2018-01-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.2246T>C at the cDNA level, p.Leu749Pro (L749P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). This variant has been reported in individuals with Lynch-associated cancers, including several who met Amsterdam criteria and/or whose tumor testing demonstrated absence of MLH1 on immunohistochemistry (IHC) and/or microsatellite instability (Colombino 2003, Losi 2005, de Leon 2007, Pedroni 2007, Perera 2010, Colombino 2011, Raymond 2013, Dudley 2015, Magnani 2015). In vitro functional studies revealed this variant to have reduced mismatch repair activity compared to wild-type (Kosinki 2010, Borras 2012, Hinrichsen 2013). Protein expression assays by Kosinski et al. (2010) and Hinrichsen et al. (2013) demonstrate MLH1 Leu749Pro to have MLH1 levels similar to wild-type, but decreased PMS2 levels suggesting a defect in the MLH1-PMS2 heterodimer. Other analyses show significantly decreased expression levels of both MLH1 and PMS2, supporting a defect in stability (Borras 2012). MLH1 Leu749Pro was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MLH1 Leu749Pro to be pathogenic.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075583 SCV000106580 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
Invitae RCV000627694 SCV000543529 likely pathogenic Hereditary nonpolyposis colon cancer 2018-10-18 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 749 of the MLH1 protein (p.Leu749Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (rs267607894, ExAC no frequency). This variant has been described in several individuals affected with Lynch syndrome and colorectal cancer (PMID: 14504054, 20864636, 21286667, 23752102, 26557847, 16181381). ClinVar contains an entry for this variant (Variation ID: 90097). Experimental studies have shown that this missense change severely impairs DNA mismatch repair activity (PMID: 20533529, 22736432, 23403630). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478074 SCV000888178 pathogenic not provided 2016-06-01 criteria provided, single submitter clinical testing

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