3-37025817-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000231790.8(MLH1):c.1219C>T(p.Gln407Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
MLH1
ENST00000231790.8 stop_gained
ENST00000231790.8 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.187
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-37025817-C-T is Pathogenic according to our data. Variant chr3-37025817-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-37025817-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MLH1 | NM_000249.4 | c.1219C>T | p.Gln407Ter | stop_gained | 12/19 | ENST00000231790.8 | NP_000240.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | c.1219C>T | p.Gln407Ter | stop_gained | 12/19 | 1 | NM_000249.4 | ENSP00000231790 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
GnomAD4 genome
Cov.:
31
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 28, 2024 | PP4, PM2, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 21, 2020 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with MLH1-related cancers (Guindalini 2015, Lagerstedt-Robinson 2016); This variant is associated with the following publications: (PMID: 28984303, 27601186, 26248088, 30989425) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 07, 2018 | The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and not found in general population data. - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 07, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 10, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The observed stop gained c.1219C>T(p.Gln407Ter) variant in MLH1 gene has been reported previously in heterozygous state in individual(s) affected with colorectal cancer and Lynch syndrome (Lagerstedt-Robinson et al., 2016). This variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (Thompson et al., 2014). For these reasons, this variant has been classified as Likely Pathogenic. Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 28, 2023 | The p.Q407* pathogenic mutation (also known as c.1219C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide position 1219. This changes the amino acid from a glutamine to a stop codon within coding exon 12. This alteration has been seen in multiple Lynch syndrome patients and families (Guindalini RS et al. Gastroenterology, 2015 Nov;149:1446-53; Lagerstedt-Robinson K et al. Oncol. Rep., 2016 Nov;36:2823-2835). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 15, 2023 | This variant changes 1 nucleotide in exon 12 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome or Lynch-syndrome associated cancer (PMID: 26248088, 27601186, 30989425). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Hereditary nonpolyposis colon cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 23, 2021 | Variant summary: MLH1 c.1219C>T (p.Gln407X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251336 control chromosomes. c.1219C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and suspected HNPCC (Guindalini_2015, Lagerstedt-Robinson_2016, Xicola_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Lynch syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This variant changes 1 nucleotide in exon 12 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals and families affected with Lynch syndrome or Lynch-syndrome associated cancer (PMID: 26248088, 27601186, 30989425). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 30, 2023 | This sequence change creates a premature translational stop signal (p.Gln407*) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with sebaceous gland cancer and colorectal cancer and Lynch syndrome (PMID: 26248088, 27601186). ClinVar contains an entry for this variant (Variation ID: 371799). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at