ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2T>C (p.Met1Thr)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.2T>C (p.Met1Thr)
Variation ID: 90135 Accession: VCV000090135.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993549 (GRCh38) [ NCBI UCSC ] 3: 37035040 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 24, 2015 Feb 14, 2024 Dec 14, 2016 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- M1T
- Other names
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- Canonical SPDI
- NC_000003.12:36993548:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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MLH1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
5531 | 5586 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (1) |
reviewed by expert panel
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Dec 14, 2016 | RCV000075621.3 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Jun 20, 2022 | RCV002288572.1 | |
Pathogenic (1) |
criteria provided, single submitter
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May 31, 2021 | RCV001800370.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Sep 24, 2021 | RCV002433577.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 26, 2023 | RCV003593883.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 14, 2016)
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reviewed by expert panel
Method: curation
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Lynch syndrome 1
Affected status: yes
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106623.5
First in ClinVar: Dec 19, 2013 Last updated: Sep 03, 2023 |
Comment:
variant in initiation codon
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Pathogenic
(Sep 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002750769.2
First in ClinVar: Nov 29, 2022 Last updated: Sep 03, 2023 |
Comment:
The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the MLH1 gene and results from a T to C … (more)
The p.M1? pathogenic mutation (also known as c.2T>C) is located in coding exon 1 of the MLH1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This variant has been reported in two colorectal cancer patients (Canard et al. Ann Surg Oncol. 2012. 19(3):809-16); van Lier et al. J Pathol. 2012. 226(5):764-74). This variant has also been reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(May 31, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV002046192.2
First in ClinVar: Jan 03, 2022 Last updated: Sep 03, 2023 |
Comment:
This variant is located in the translation initiation codon of the MLH1 mRNA and is predicted to interfere with MLH1 protein synthesis. The variant has … (more)
This variant is located in the translation initiation codon of the MLH1 mRNA and is predicted to interfere with MLH1 protein synthesis. The variant has been reported in individuals affected with Lynch syndrome and colorectal cancer in the published literature (PMID: 22081473 (2012), 21879275 (2012)). In addition, a functional study demonstrated that abolishing the canonical start site in the MLH1 gene significantly reduces expression (PMID: 24302565 (2015)). Based on the available information, this variant is classified as pathogenic. (less)
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Likely pathogenic
(Jun 20, 2022)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002580928.2
First in ClinVar: Oct 15, 2022 Last updated: Sep 03, 2023 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Mar 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Hereditary nonpolyposis colorectal neoplasms
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV004293443.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects MLH1 function (PMID: 24302565). … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that disruption of the initiator codon affects MLH1 function (PMID: 24302565). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90135). Disruption of the initiator codon has been observed in individuals with Lynch syndrome (PMID: 12624141, 16807412, 21879275, 22081473, 24302565). This variant is present in population databases (rs111052004, gnomAD 0.0009%). This sequence change affects the initiator methionine of the MLH1 mRNA. The next in-frame methionine is located at codon 35. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
A Novel MLH1 Initiation Codon Mutation (c.3G>T) in a Large Chinese Lynch Syndrome Family with Different Onset Age and mRNA Expression Level. | Zhang Y | BioMed research international | 2018 | PMID: 30539002 |
Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity. | Parsons MT | Molecular carcinogenesis | 2015 | PMID: 24302565 |
Yield of routine molecular analyses in colorectal cancer patients ≤70 years to detect underlying Lynch syndrome. | van Lier MG | The Journal of pathology | 2012 | PMID: 22081473 |
Screening for Lynch syndrome in colorectal cancer: are we doing enough? | Canard G | Annals of surgical oncology | 2012 | PMID: 21879275 |
Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. | Barnetson RA | The New England journal of medicine | 2006 | PMID: 16807412 |
Cancer risk in 348 French MSH2 or MLH1 gene carriers. | Parc Y | Journal of medical genetics | 2003 | PMID: 12624141 |
http://www.insight-database.org/classifications/?gene=MLH1&variant=c.2T%3EC | - | - | - | - |
Text-mined citations for rs111052004 ...
HelpRecord last updated Feb 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.