ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1989G>T (p.Glu663Asp) (rs63751662)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075462 SCV000106459 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration, interrupting functional domain (full inactivation of variant allele)
Invitae RCV000524264 SCV000260926 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 663 of the MLH1 protein (p.Glu663Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant also falls at the last nucleotide of exon 17 of the MLH1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with Lynch syndrome (PMID: 10480359, 16395668, 21642682, 24278394, 21404117). ClinVar contains an entry for this variant (Variation ID: 89980). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing. RT-PCR and minigene analyses of patient lymphoblast RNA confirm these predictions, showing that this variant leads to skipping of exon 17 (PMID: 10480359, 16395668, 18561205), although an experimental study in yeast showed wild type like mismatch repair activity and expression of this variant (PMID: 17510385). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000256174 SCV000321899 pathogenic not provided 2018-01-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1989G>T at the cDNA level. Located in the last nucleotide of exon 17, this variant is predicted by multiple slicing based models to damage the natural splice donor site and cause abnormal splicing. Both Auclair et al. (2006) and Tournier et al. (2008) confirm, via RNA based studies, that MLH1 c.1989G>T causes skipping of exon 17 by activating a cryptic donor splice site. The resulting skipping of exon 17 is expected to be in-frame, however, this interrupts the domain of interaction with PMS2/MLH3/PMS1 (Raevaara 2005). This variant has been reported in multiple individuals with colon and/or other Lynch syndrome-related cancers, many of whose tumors are reported to show absence of the MLH1 protein via mismatch repair immunohistochemistry (MMR IHC) and/or have been found to be microsatellite (MSI) unstable (Wang 1999 Bonadona 2011, Hardt 2011, De Lellis 2013, Magnani 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Although the nucleotide substitution results in the change of a Glutamic acid to an Aspartic acid at codon 663, and is called Glu663Asp in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. MLH1 c.1989G>T was not observed in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 1989, is conserved across species. Based on the current evidence, we consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000075462 SCV000592432 likely pathogenic Lynch syndrome 2013-12-16 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000256174 SCV000601378 pathogenic not provided 2017-01-17 criteria provided, single submitter clinical testing

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