ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.74T>C (p.Ile25Thr)
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.74T>C (p.Ile25Thr)
Variation ID: 1365650 Accession: VCV001365650.8
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 36993621 (GRCh38) [ NCBI UCSC ] 3: 37035112 (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 28, 2022 May 1, 2024 Oct 29, 2023 - HGVS
- ... more HGVS ... less HGVS
- Protein change
- I25T
- Other names
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- Canonical SPDI
- NC_000003.12:36993620: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
Help
The frequency of the allele represented by this VCV record.
The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
- Links
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
Help
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 |
5624 | 5679 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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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Uncertain significance (1) |
criteria provided, single submitter
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Oct 29, 2023 | RCV001961868.5 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jun 13, 2023 | RCV003299072.2 | |
MLH1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Sep 6, 2022 | RCV003426225.4 |
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
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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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Uncertain significance
(Sep 06, 2022)
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criteria provided, single submitter
Method: clinical testing
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MLH1-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004117611.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The MLH1 c.74T>C variant is predicted to result in the amino acid substitution p.Ile25Thr. This variant has not been reported in individual(s) with MLH1-related diseases. … (more)
The MLH1 c.74T>C variant is predicted to result in the amino acid substitution p.Ile25Thr. This variant has not been reported in individual(s) with MLH1-related diseases. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37035112-T-C) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/1365650/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Oct 29, 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: SCV002134776.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the MLH1 protein (p.Ile25Thr). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 25 of the MLH1 protein (p.Ile25Thr). This variant is present in population databases (rs63750514, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 1365650). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 17210669, 17510385, 31697235). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jun 13, 2023)
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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: SCV004006431.2
First in ClinVar: Jul 08, 2023 Last updated: May 01, 2024 |
Comment:
The p.I25T variant (also known as c.74T>C), located in coding exon 1 of the MLH1 gene, results from a T to C substitution at nucleotide … (more)
The p.I25T variant (also known as c.74T>C), located in coding exon 1 of the MLH1 gene, results from a T to C substitution at nucleotide position 74. The isoleucine at codon 25 is replaced by threonine, an amino acid with similar properties. This variant was present in a family meeting Amsterdam criteria but demonstrated a dominant mutator effect and was considered MMR-proficient in vitro (Takahashi M et al. Cancer Res, 2007 May;67:4595-604). In yeast-based functional assay, the MLH1 I25T equivalent demonstrated an intermediate mutator phenotype but was considered associated with HNPCC by authors (Wanat JJ et al. Hum Mol Genet, 2007 Feb;16:445-52). Additionally, this alteration showed a steady-state cellular level of MLH1 that was 51% of wild type and potential protein destabilization (Abildgaard AB et al. Elife, 2019 Nov;8:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (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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Computational and cellular studies reveal structural destabilization and degradation of MLH1 variants in Lynch syndrome. | Abildgaard AB | eLife | 2019 | PMID: 31697235 |
LOVD v.2.0: the next generation in gene variant databases. | Fokkema IF | Human mutation | 2011 | PMID: 21520333 |
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. | Takahashi M | Cancer research | 2007 | PMID: 17510385 |
The effect of genetic background on the function of Saccharomyces cerevisiae mlh1 alleles that correspond to HNPCC missense mutations. | Wanat JJ | Human molecular genetics | 2007 | PMID: 17210669 |
Text-mined citations for rs63750514 ...
HelpRecord last updated May 19, 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.