ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.1745T>A (p.Leu582His)
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.1745T>A (p.Leu582His)
Variation ID: 1779284 Accession: VCV001779284.2
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37047532 (GRCh38) [ NCBI UCSC ] 3: 37089023 (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 Nov 29, 2022 May 1, 2024 Dec 21, 2016 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.1745T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Leu582His missense NM_001167617.3:c.1451T>A NP_001161089.1:p.Leu484His missense NM_001167618.3:c.1022T>A NP_001161090.1:p.Leu341His missense NM_001167619.3:c.1022T>A NP_001161091.1:p.Leu341His missense NM_001258271.2:c.1745T>A NP_001245200.1:p.Leu582His missense NM_001258273.2:c.1022T>A NP_001245202.1:p.Leu341His missense NM_001258274.3:c.1022T>A NP_001245203.1:p.Leu341His missense NM_001354615.2:c.1022T>A NP_001341544.1:p.Leu341His missense NM_001354616.2:c.1022T>A NP_001341545.1:p.Leu341His missense NM_001354617.2:c.1022T>A NP_001341546.1:p.Leu341His missense NM_001354618.2:c.1022T>A NP_001341547.1:p.Leu341His missense NM_001354619.2:c.1022T>A NP_001341548.1:p.Leu341His missense NM_001354620.2:c.1451T>A NP_001341549.1:p.Leu484His missense NM_001354621.2:c.722T>A NP_001341550.1:p.Leu241His missense NM_001354622.2:c.722T>A NP_001341551.1:p.Leu241His missense NM_001354623.2:c.722T>A NP_001341552.1:p.Leu241His missense NM_001354624.2:c.671T>A NP_001341553.1:p.Leu224His missense NM_001354625.2:c.671T>A NP_001341554.1:p.Leu224His missense NM_001354626.2:c.671T>A NP_001341555.1:p.Leu224His missense NM_001354627.2:c.671T>A NP_001341556.1:p.Leu224His missense NM_001354628.2:c.1745T>A NP_001341557.1:p.Leu582His missense NM_001354629.2:c.1646T>A NP_001341558.1:p.Leu549His missense NM_001354630.2:c.1732-985T>A intron variant NC_000003.12:g.37047532T>A NC_000003.11:g.37089023T>A NG_007109.2:g.59183T>A LRG_216:g.59183T>A LRG_216t1:c.1745T>A LRG_216p1:p.Leu582His - Protein change
- L484H, L582H, L224H, L241H, L341H, L549H
- Other names
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- Canonical SPDI
- NC_000003.12:37047531:T:A
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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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- Links
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 |
5689 | 5749 |
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) |
criteria provided, single submitter
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Dec 21, 2016 | RCV002401483.2 |
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
(Dec 21, 2016)
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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: SCV002710290.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.L582H pathogenic mutation (also known as c.1745T>A), located in coding exon 16 of the MLH1 gene, results from a T to A substitution at … (more)
The p.L582H pathogenic mutation (also known as c.1745T>A), located in coding exon 16 of the MLH1 gene, results from a T to A substitution at nucleotide position 1745. The leucine at codon 582 is replaced by histidine, an amino acid with similar properties. This alteration was reported in several families meeting Amsterdam II criteria (Ambry internal data; Universal Mutation Database [available from www.umd.be]). Based on internal assessment, this alteration destabilizes the fold of the C-terminal exonuclease domain, with magnitude of destabilization equal to or greater than that of nearby pathogenic alterations (Dombrovsky, L., et al., unpublished structure PDB: 3RBN). A different alteration at the same codon, p.L582P, has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson B et al. Hum Mutat. 2013 Jan;34(1):200-9; Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. The p.L582H alteration is predicted to be probably damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (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
HelpThere are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar. |
Text-mined citations for this variant ...
HelpRecord last updated May 01, 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.