chr3-37048994-GA-TC
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_000249.4(MLH1):c.2080_2081delGAinsTC(p.Glu694Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
MLH1
NM_000249.4 missense
NM_000249.4 missense
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.05
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 25, 2023 | This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which replaces glutamic acid with serine at codon 694 of the MLH1 protein. This substitution changes two basepairs, c.2080G>T and c.2081A>C, which together changes the codon for glutamic acid (GAG) to one for serine (TCG). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset, microsatellite unstable colorectal cancer (PMID: 33753878), as well as in an individual affected with sarcoma who also carried a pathogenic variant in the BRCA2 gene (PMID: 25712765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2023 | The c.2080_2081delGAinsTC variant (also known as p.E694S), located in coding exon 18 of the MLH1 gene, results from an in-frame deletion of GA and insertion of TC at nucleotide positions 2080 to 2081. This results in the substitution of the glutamic acid residue for a serine residue at codon 694, an amino acid with similar properties. This alteration has been identified in a patient whose colon tumor demonstrated microsatellite instability, absent MLH1 staining by IHC, and loss of heterozygosity (Kim JE et al. Exp Mol Med, 2021 Mar;53:446-456). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 16, 2023 | Variant summary: MLH1 c.2080_2081delinsTC (p.Glu694Ser) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. This variant is reported as two separate single nucleotide changes in gnomAD, with both variants found in the same subpopulations with the same number of occurrences, and read data demonstrating that both of these SNPs occurred together in cis, in 3 cases. Therefore the variant allele was found at a frequency of 2e-05 in 251054 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2080_2081delinsTC has been reported in the literature in an individual affected with sarcoma, who also carried a BRCA2 pathogenic allele (Varga_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25712765). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2024 | - - |
Lynch syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This variant causes a deletion of GA and insertion of TC at nucleotide positions 2080 and 2081 in exon 18 of the MLH1 gene, which replaces glutamic acid with serine at codon 694 of the MLH1 protein. This substitution changes two basepairs, c.2080G>T and c.2081A>C, which together changes the codon for glutamic acid (GAG) to one for serine (TCG). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with early onset, microsatellite unstable colorectal cancer (PMID: 33753878), as well as in an individual affected with sarcoma who also carried a pathogenic variant in the BRCA2 gene (PMID: 25712765). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 28, 2023 | Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Observed in an individual with sarcoma who also carried a pathogenic variant in BRCA2 (Varga et al., 2015); This variant is associated with the following publications: (PMID: 23695190, 25712765, 12799449, 20533529, 22753075) - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2024 | - - |
Computational scores
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Calibrated prediction
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at