rs63751012
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000249.4(MLH1):c.109G>A(p.Glu37Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E37G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000249.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MLH1 | NM_000249.4 | c.109G>A | p.Glu37Lys | missense_variant | 1/19 | ENST00000231790.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MLH1 | ENST00000231790.8 | c.109G>A | p.Glu37Lys | missense_variant | 1/19 | 1 | NM_000249.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461830Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727216
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 10, 2023 | 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]. - |
Carcinoma of colon Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Lynch syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | May 01, 2018 | 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. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 14, 2024 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at