ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1A>G (p.Met1Val)
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.1A>G (p.Met1Val)
Variation ID: 89994 Accession: VCV000089994.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993548 (GRCh38) [ NCBI UCSC ] 3: 37035039 (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 Sep 15, 2018 Feb 14, 2024 Jun 30, 2017 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- M1V
- Other names
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- Canonical SPDI
- NC_000003.12:36993547:A:G
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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.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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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 |
5564 | 5619 |
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
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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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Jun 30, 2017 | RCV000075477.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Dec 27, 2020 | RCV000629832.4 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 16, 2019 | RCV002415530.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Nov 7, 2022 | RCV003477467.1 |
Submissions - Germline
Classification
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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
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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
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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
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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
(Jun 30, 2017)
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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: SCV000106473.5
First in ClinVar: Dec 19, 2013 Last updated: Sep 03, 2023 |
Comment:
MLH1 initiation codon variant
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Pathogenic
(Apr 16, 2019)
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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: SCV002721813.2
First in ClinVar: Nov 29, 2022 Last updated: Sep 03, 2023 |
Comment:
The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the MLH1 gene, results from an A to G substitution at … (more)
The p.M1? pathogenic mutation (also known as c.1A>G), located in coding exon 1 of the MLH1 gene, results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. There is an in-frame methionine 35 amino acids downstream from this initiation site. The N-terminus of MLH1 is known to be functionally and structurally important (Ambry internal analysis; Tempel W et al. Structural Genomics Consortium. PDB ID: 4P7A Crystal Structure of human MLH1). One functional assay demonstrated that the c.1A>G allele encodes an in-frame protein lacking the first 34 amino acids resulting in deficient mismatch repair activity similar to that of a known pathogenic missense alteration (Parsons MT et al. Mol. Carcinog. 2015 Jul;54:513-22). Additionally, this mutation has been reported in several individuals with HNPCC (Scott RJ et al. Am. J. Hum. Genet. 2001 Jan;68:118-127; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31), including an individual meeting Amsterdam criteria (Parsons MT et al. Mol. Carcinog., 2015 Jul;54:513-22). This mutation has been identified in conjunction with MLH1 loss of heterozygosity (LOH) in an MMR deficient tumor, supporting pathogenicity (Shirts BH et al. Am. J. Hum. Genet. 2018 Jul;103:19-29). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Dec 27, 2020)
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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: SCV000750788.5
First in ClinVar: May 28, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant significantly reduces protein expression, likely affecting translation initiation … (more)
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant significantly reduces protein expression, likely affecting translation initiation (PMID: 24302565). The next in-frame methionine is found at codon 35, and experimental studies demonstrate that this alternate start codon produces protein levels comparable to the wild-type allele. However, the functional capacity of the variant protein missing the first 34 amino acids is equivalent to known MMR deficient variants, suggesting that the first 34 amino acids are critical for normal protein function (PMID: 24302565). This variant has been reported in individuals affected with Lynch syndrome (PMID: 24302565, 11112663) and colorectal cancer (PMID: 28944238). ClinVar contains an entry for this variant (Variation ID: 89994). This variant is not present in population databases (ExAC no frequency). 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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Pathogenic
(Nov 07, 2022)
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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: SCV004220864.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
This variant disrupts the translation initiation codon of the MLH1 mRNA and is predicted to interfere with MLH1 protein synthesis. This variant has not been … (more)
This variant disrupts the translation initiation codon of the MLH1 mRNA and is predicted to interfere with MLH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with MLH1 related disease (PMID: 11112663 (2001), 24302565 (2015), 9298827 (1997)). This variant was also found to reduce protein expression and MMR efficacy (PMID: 24302565 (2015)). Based on the available information, this variant is classified as pathogenic. (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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Using Somatic Mutations from Tumors to Classify Variants in Mismatch Repair Genes. | Shirts BH | American journal of human genetics | 2018 | PMID: 29887214 |
Lynch syndrome mutation spectrum in New South Wales, Australia, including 55 novel mutations. | Sjursen W | Molecular genetics & genomic medicine | 2016 | PMID: 27064304 |
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 |
Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. | Scott RJ | American journal of human genetics | 2001 | PMID: 11112663 |
Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes. | Wehner M | Human mutation | 1997 | PMID: 9298827 |
http://www.insight-database.org/classifications/?gene=MLH1&variant=c.1A%3EG | - | - | - | - |
Text-mined citations for rs587778967 ...
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.