ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2242G>C (p.Asp748His)
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.
Uncertain significance(5); Likely benign(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.2242G>C (p.Asp748His)
Variation ID: 405434 Accession: VCV000405434.17
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37050624 (GRCh38) [ NCBI UCSC ] 3: 37092115 (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 Apr 17, 2017 Jul 23, 2024 Apr 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.2242G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Asp748His missense NM_001167617.3:c.1948G>C NP_001161089.1:p.Asp650His missense NM_001167618.3:c.1519G>C NP_001161090.1:p.Asp507His missense NM_001167619.3:c.1519G>C NP_001161091.1:p.Asp507His missense NM_001258271.2:c.2035G>C NP_001245200.1:p.Asp679His missense NM_001258273.2:c.1519G>C NP_001245202.1:p.Asp507His missense NM_001258274.3:c.1519G>C NP_001245203.1:p.Asp507His missense NM_001354615.2:c.1519G>C NP_001341544.1:p.Asp507His missense NM_001354616.2:c.1519G>C NP_001341545.1:p.Asp507His missense NM_001354617.2:c.1519G>C NP_001341546.1:p.Asp507His missense NM_001354618.2:c.1519G>C NP_001341547.1:p.Asp507His missense NM_001354619.2:c.1519G>C NP_001341548.1:p.Asp507His missense NM_001354620.2:c.1948G>C NP_001341549.1:p.Asp650His missense NM_001354621.2:c.1219G>C NP_001341550.1:p.Asp407His missense NM_001354622.2:c.1219G>C NP_001341551.1:p.Asp407His missense NM_001354623.2:c.1219G>C NP_001341552.1:p.Asp407His missense NM_001354624.2:c.1168G>C NP_001341553.1:p.Asp390His missense NM_001354625.2:c.1168G>C NP_001341554.1:p.Asp390His missense NM_001354626.2:c.1168G>C NP_001341555.1:p.Asp390His missense NM_001354627.2:c.1168G>C NP_001341556.1:p.Asp390His missense NM_001354628.2:c.2149G>C NP_001341557.1:p.Asp717His missense NM_001354629.2:c.2143G>C NP_001341558.1:p.Asp715His missense NM_001354630.2:c.2077G>C NP_001341559.1:p.Asp693His missense NC_000003.12:g.37050624G>C NC_000003.11:g.37092115G>C NG_007109.2:g.62275G>C LRG_216:g.62275G>C LRG_216t1:c.2242G>C LRG_216p1:p.Asp748His - Protein change
- D748H, D717H, D390H, D679H, D407H, D507H, D715H, D650H, D693H
- Other names
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- Canonical SPDI
- NC_000003.12:37050623:G: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
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
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 |
5687 | 5747 |
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
Help
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 13, 2023 | RCV000464953.7 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Dec 5, 2023 | RCV000776448.7 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Apr 29, 2024 | RCV003153596.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 20, 2023 | RCV004000666.2 |
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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Uncertain significance
(Dec 19, 2022)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
germline
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St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003842969.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
The MLH1 c.2242G>C (p.Asp748His) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious … (more)
The MLH1 c.2242G>C (p.Asp748His) missense change has a maximum subpopulation frequency of 0.00088% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. In a case-control study, this variant was detected in 0 of 165 individuals with colorectal cancer and/or polyposis and 1 of 2512 control individuals (PMID: 30267214). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
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Uncertain significance
(Apr 18, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000911980.3
First in ClinVar: May 20, 2019 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces aspartic acid with histidine at codon 748 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces aspartic acid with histidine at codon 748 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/251302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Oct 13, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000543657.7
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 748 of the MLH1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 748 of the MLH1 protein (p.Asp748His). This variant is present in population databases (rs374380262, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 405434). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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
(Nov 20, 2023)
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criteria provided, single submitter
Method: clinical testing
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Lynch syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004843300.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces aspartic acid with histidine at codon 748 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces aspartic acid with histidine at codon 748 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/251302 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 2
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Uncertain significance
(Dec 05, 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: SCV001175676.4
First in ClinVar: Mar 16, 2020 Last updated: May 01, 2024 |
Comment:
The p.D748H variant (also known as c.2242G>C), located in coding exon 19 of the MLH1 gene, results from a G to C substitution at nucleotide … (more)
The p.D748H variant (also known as c.2242G>C), located in coding exon 19 of the MLH1 gene, results from a G to C substitution at nucleotide position 2242. The aspartic acid at codon 748 is replaced by histidine, an amino acid with similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). 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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Likely benign
(Apr 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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Colorectal cancer, hereditary nonpolyposis, type 2
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV005084022.1
First in ClinVar: Jul 23, 2024 Last updated: Jul 23, 2024 |
Comment:
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic … (more)
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. (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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Rare loss of function variants in candidate genes and risk of colorectal cancer. | Rosenthal EA | Human genetics | 2018 | PMID: 30267214 |
Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm. | Morris B | BMC genetics | 2016 | PMID: 27363726 |
Text-mined citations for rs374380262 ...
HelpRecord last updated Sep 29, 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.