chr3-37028833-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.1459C>T(p.Arg487Ter) 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. R487R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
MLH1
ENST00000231790.8 stop_gained
ENST00000231790.8 stop_gained
Scores
2
2
3
Clinical Significance
Conservation
PhyloP100: 0.641
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 3-37028833-C-T is Pathogenic according to our data. Variant chr3-37028833-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 89744.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37028833-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.1459C>T | p.Arg487Ter | stop_gained | 13/19 | ENST00000231790.8 | NP_000240.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | c.1459C>T | p.Arg487Ter | stop_gained | 13/19 | 1 | NM_000249.4 | ENSP00000231790 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:23
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 09, 2023 | 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 at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 15222003, 24344984, 27601186, 24333619, 10713887, 17473388, 31830689, 15870828, 9777949, 15849733, 24278394, 15996210, 21636617, 17312306, 16181381, 17505997, 18726168, 15713769, 22776989, 28874130, 27064304, 11920650, 10995807, 26437257, 30521064, 30322717, 31350202, 31589614, 30787465, 31494577, 31844177, 31118792, 14635101, 30077346, 21681552, 20233461, 33532831, 36073830) - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 25, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 26, 2020 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Feb 11, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 15, 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 | Baylor Genetics | Jul 20, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 05, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 17, 2017 | - - |
Lynch syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2016 | Variant summary: The MLH1 c.1459C>T (p.Arg487X) variant results in a premature termination codon, predicted to cause a truncated or absent MLH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 22, 2024 | This variant changes 1 nucleotide in exon 13 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with colorectal cancer and/or Lynch syndrome (PMID: 10713887, 10995807, 11920650, 14635101, 15849733, 16181381, 18726168, 21636617, 21681552, 22776989, 27064304, 27300552, 27601186, 30521064, 31118792). 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. - |
| Pathogenic, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | Jan 30, 2019 | - - |
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Coding sequence variation resulting in a stop codon - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 10, 2022 | The p.R487* pathogenic mutation (also known as c.1459C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1459. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome; several with family histories meeting Amsterdam criteria and whose tumors demonstrated high microsatellite instability and/or loss of MLH1/PMS2 on immunohistochemistry (IHC) (Fidalgo P et al. Eur. J. Hum. Genet. 2000 Jan;8:49-53; Pigatto F et al. Hered Cancer Clin Pract, 2004 Nov;2:175-84; Casey G et al. JAMA. 2005 Feb;293:799-809; Mangold E et al. Int. J. Cancer. 2005 Sep;116:692-702; Yap HL et al. Fam. Cancer. 2009 Aug;8:85-94; Win AK et al. J. Med. Genet. 2011 Aug;48:530-4; De Lellis L et al. PLoS One, 2013 Nov;8:e81194; Carneiro da Silva F et al. PLoS One, 2015 Oct;10:e0139753; Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; Roberts ME et al. Genet Med, 2018 10;20:1167-1174; Lee J et al. Gynecol Oncol, 2018 10;151:153-158; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739). 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 | Jan 09, 2023 | This variant changes 1 nucleotide in exon 13 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in multiple individuals and families affected with colorectal cancer and/or Lynch syndrome (PMID: 10713887, 10995807, 11920650, 14635101, 15849733, 16181381, 18726168, 21636617, 21681552, 22776989, 27064304, 27300552, 27601186, 30521064, 31118792). 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. - |
Carcinoma of colon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The MLH1 p.Arg487X variant was identified in 14 of 7202 proband chromosomes (frequency: 0.002) from individuals or families with Lynch Syndrome (Caldes 2002, Casey 2005, DeLeon 2007, Fidalgo 2000, Lage 2004, Lee 2005, Leung 1998, Losi 2005, Mangold 2005, Mangold 2005, Pedroni 2007, Peel 2000, Lagerstedt Robinson 2007). The variant was also previously identified by our laboratory in 2 individuals with Lynch Syndrome. The variant was identified in dbSNP (ID: rs63749795), “With Pathogenic allele”, COSMIC 1X, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database” as class 5 - pathogenic, “Zhejiang Colon Cancer Database” as “pathogenic”, ClinVar database (submitted by “InSiGHT”), and UMD (27 X as a causal variant). A tumour with the variant was also identified as MLH1 deficient and MSI-H (within the “InSiGHT Colon Cancer Database”), and tumours described in the literature also demonstrated microsatellite instability and/or deficiency of MLH1 by immunohistochemistry (Caldes 2002, Casey 2005, Lagerstedt Robinson 2007, Lee 2005, Losi 2005, Mangold 2005, Pedroni 2007). The p.Arg487X variant leads to a premature stop codon at position 487, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the MLH1 gene are an established mechanism of disease in Lynch syndrome and this is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Lynch syndrome 1 Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Ding PR Lab, Sun Yat-sen University Cancer Center | - | - - |
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Lynch-like syndrome Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
MLH1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 06, 2024 | The MLH1 c.1459C>T variant is predicted to result in premature protein termination (p.Arg487*). This variant has been reported as pathogenic in patients with colorectal and ovarian cancer (Rossi et al. 2017. PubMed ID: 28874130; Jiang et al. 2019. PubMed ID: 30521064; Dominguez-Valentin et al. 2013. PubMed ID: 24344984; Lagerstedt-Robinson et al. 2016. PubMed ID: 27601186; Table S1, Carter et al. 2018. PubMed ID: 30322717). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/89744/). Nonsense variants in MLH1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2023 | This sequence change creates a premature translational stop signal (p.Arg487*) 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 colorectal cancer and Lynch syndrome (PMID: 10713887, 14635101, 15849733, 15870828, 21636617, 21681552, 24344984). ClinVar contains an entry for this variant (Variation ID: 89744). 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