3-37028833-C-T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000249.4(MLH1):c.1459C>T(p.Arg487*) 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
Consequence
NM_000249.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- Lynch syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
- Lynch syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
- Muir-Torre syndromeInheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
- mismatch repair cancer syndrome 1Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
- Lynch syndrome 1Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- ovarian cancerInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- malignant pancreatic neoplasmInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- rhabdomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- prostate cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- breast cancerInheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| MLH1 | NM_000249.4 | c.1459C>T | p.Arg487* | stop_gained | Exon 13 of 19 | ENST00000231790.8 | NP_000240.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| MLH1 | ENST00000231790.8 | c.1459C>T | p.Arg487* | stop_gained | Exon 13 of 19 | 1 | NM_000249.4 | ENSP00000231790.3 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:7
- -
- -
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. -
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) -
- -
- -
- -
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:4
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
- -
- -
Lynch syndrome Pathogenic:4
Coding sequence variation resulting in a stop codon -
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. -
- -
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. -
Hereditary cancer-predisposing syndrome Pathogenic:3
PVS1, PM2_Supporting, PP4_Moderate c.1459C>T, located in exon 13 of the MLH1 gene, is a nonsense variant expected to result in loss of function by premature protein truncation before codon 753, p.(Arg487*) (PVS1). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been identified in many colorectal and/or endometrial tumors showing microsatellite instability and/or loss of MLH1 expression by IHC, and in at least 2 cases, the absence of somatic MLH1 methylation was confirmed (internal data, PMIDs: 20233461, 15713769, 17312306, among others) (PP4_Moderate). This variant has been reported in ClinVar (22x pathogenic), in LOVD (28x pathogenic, 39x uncertain significance) and in InSiGHT databases (Class 5: pathogenic; Summary Justification: Coding sequence variation resulting in a stop codon; 2013/09/05 v1.9). Based on currently available information, the variant c.1459C>T should be considered a pathogenic variant. -
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. -
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). 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. -
Carcinoma of colon Pathogenic:1
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
- -
Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Pathogenic:1
- -
Lynch-like syndrome Pathogenic:1
- -
MLH1-related disorder Pathogenic:1
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
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). Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 89744). 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