ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.113A>G (p.Asn38Ser)
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.113A>G (p.Asn38Ser)
Variation ID: 89648 Accession: VCV000089648.4
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993660 (GRCh38) [ NCBI UCSC ] 3: 37035151 (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 Sep 5, 2013 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- N38S
- Other names
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- Canonical SPDI
- NC_000003.12:36993659: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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Sep 5, 2013 | RCV000075118.3 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV000688444.3 |
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
(Sep 05, 2013)
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reviewed by expert panel
Method: research
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Lynch Syndrome
Affected status: unknown
Allele origin:
germline
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International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Accession: SCV000106109.3
First in ClinVar: Dec 19, 2013 Last updated: Dec 24, 2022 |
Comment:
Multifactorial likelihood analysis posterior probability >0.99
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Pathogenic
(Jan 08, 2024)
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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: SCV000816054.3
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 38 of the MLH1 protein (p.Asn38Ser). … (more)
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 38 of the MLH1 protein (p.Asn38Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Lynch syndrome (PMID: 15713769, 26895986). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89648). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MLH1 function (PMID: 15475387, 22949379). This variant disrupts the p.Asn38 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12373605, 20020535, 20704743, 23403630). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been 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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Germline mutations in PMS2 and MLH1 in individuals with solitary loss of PMS2 expression in colorectal carcinomas from the Colon Cancer Family Registry Cohort. | Rosty C | BMJ open | 2016 | PMID: 26895986 |
Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. | Hinrichsen I | Clinical cancer research : an official journal of the American Association for Cancer Research | 2013 | PMID: 23403630 |
A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry. | Thompson BA | Human mutation | 2013 | PMID: 22949379 |
A novel pathogenic MLH1 missense mutation, c.112A > C, p.Asn38His, in six families with Lynch syndrome. | van Riel E | Hereditary cancer in clinical practice | 2010 | PMID: 20704743 |
A cell-free assay for the functional analysis of variants of the mismatch repair protein MLH1. | Drost M | Human mutation | 2010 | PMID: 20020535 |
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. | Casey G | JAMA | 2005 | PMID: 15713769 |
Human MutL homolog (MLH1) function in DNA mismatch repair: a prospective screen for missense mutations in the ATPase domain. | Ellison AR | Nucleic acids research | 2004 | PMID: 15475387 |
Genomic deletions of MSH2 and MLH1 in colorectal cancer families detected by a novel mutation detection approach. | Gille JJ | British journal of cancer | 2002 | PMID: 12373605 |
http://www.insight-database.org/classifications/index.html?gene=MLH1&variant=c.113A%3EG | - | - | - | - |
Text-mined citations for rs587778888 ...
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.