Submissions for variant NM_000249.4(MLH1):c.109G>A (p.Glu37Lys)

dbSNP: rs63751012

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000693918	SCV000822341	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 37 of the MLH1 protein (p.Glu37Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 12624141, 18415027, 27435373, 31815095; Invitae). ClinVar contains an entry for this variant (Variation ID: 89640). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 20020535, 22753075). This variant disrupts the p.Glu37 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075110	SCV000887392	pathogenic	Lynch syndrome	2018-05-01	criteria provided, single submitter	clinical testing	MLH1 NM_000249.3:c.109G>A has a 99.97% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MLH1 locus. See Shirts et al 2018, PMID 29887214.
Myriad Genetics, Inc.	RCV003451004	SCV004189286	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-10	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20020535]. This variant is expected to disrupt protein structure [Myriad internal data].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357016	SCV001552340	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The MLH1 p.Glu37Lys variant was identified in 2 of 1074 proband chromosomes (frequency: 0.002) from French individuals or families with Lynch syndrome (Bonadona 2011). Functional analysis of MMR (mismatch repair) activity in a cell free assay found the variant to have less than 20% MMR activity (Drost 2010). A bioinformatic model CADD (Combined Annotation Dependent Depletion) predicted the variant to be likely pathogenic (van der Velde 2015). In a study looking at genome-wide cnLOH (copy neutral LOH), the variant showed cnLOH at the MMR locus (3p26.3–21.31 ) when paired normal and tumour tissue was analyzed, the tumour being MSI-H, MLH1 intact and PMS2 deficient (van Puijenbroek 2008). The variant was also identified in dbSNP (ID: rs63751012) “With Pathogenic, Uncertain significance allele”, ClinVar (uncertain significance, reviewed by an expert panel (2013)), Clinvitae (1x), UMD-LSDB (32x as causal), Insight Colon Cancer Gene Variant Database (3x class 3), Mismatch Repair Genes Variant Database (1X), Insight Hereditary Tumors Database (3x class 3), and was not identified in Genesight-COGR, Cosmic, Zhejiang Colon Cancer Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Glu37 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Lys variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.