ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.121G>C (p.Asp41His) (rs267607713)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075155 SCV000106146 pathogenic Lynch syndrome I 2014-10-10 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99
GeneDx RCV000255808 SCV000321893 pathogenic not provided 2016-06-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted MLH1 c.121G>C at the cDNA level, p.Asp41His (D41H) at the protein level, and results in the change of an Aspartic Acid to a Histidine (GAT>CAT). This variant has been observed in several individuals with a history of colorectal cancer and has been shown to segregate with disease in a Spanish family meeting Amsterdam I criteria (Parc 2003, Bonnet 2012, Hinrichsen 2015, Pineda 2015). Both Pineda et al. (2015) and Bonnet et al. (2012) report that colorectal tumors from individuals found to harbor MLH1 Asp41His have been shown to be microsatellite unstable with retention of all four proteins via mismatch repair immunohistochemistry; however, it has been suggested that the retention of MLH1 in these tumors is due to a stable MLH1 protein that is catalytically inactive (Pineda 2015). Importantly, MLH1 Asp41His has been shown to result in greatly reduced mismatch repair activity in two separate in vitro based functional assays (Hinrichsen 2015, Pineda 2015). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Asp41His occurs at a position that is conserved across species and is located within a region responsible for ATP-binding and hydrolysis (Raevaara 2005, Hardt 2011). In silico analyses predict that this pathogenic variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.

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