ClinVar Genomic variation as it relates to human health
NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)
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(3)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)
Variation ID: 90090 Accession: VCV000090090.43
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 3p22.2 3: 37050592 (GRCh38) [ NCBI UCSC ] 3: 37092083 (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 Sep 16, 2024 Feb 16, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000249.4:c.2210A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000240.1:p.Asp737Val missense NM_001167617.3:c.1916A>T NP_001161089.1:p.Asp639Val missense NM_001167618.3:c.1487A>T NP_001161090.1:p.Asp496Val missense NM_001167619.3:c.1487A>T NP_001161091.1:p.Asp496Val missense NM_001258271.2:c.2003A>T NP_001245200.1:p.Asp668Val missense NM_001258273.2:c.1487A>T NP_001245202.1:p.Asp496Val missense NM_001258274.3:c.1487A>T NP_001245203.1:p.Asp496Val missense NM_001354615.2:c.1487A>T NP_001341544.1:p.Asp496Val missense NM_001354616.2:c.1487A>T NP_001341545.1:p.Asp496Val missense NM_001354617.2:c.1487A>T NP_001341546.1:p.Asp496Val missense NM_001354618.2:c.1487A>T NP_001341547.1:p.Asp496Val missense NM_001354619.2:c.1487A>T NP_001341548.1:p.Asp496Val missense NM_001354620.2:c.1916A>T NP_001341549.1:p.Asp639Val missense NM_001354621.2:c.1187A>T NP_001341550.1:p.Asp396Val missense NM_001354622.2:c.1187A>T NP_001341551.1:p.Asp396Val missense NM_001354623.2:c.1187A>T NP_001341552.1:p.Asp396Val missense NM_001354624.2:c.1136A>T NP_001341553.1:p.Asp379Val missense NM_001354625.2:c.1136A>T NP_001341554.1:p.Asp379Val missense NM_001354626.2:c.1136A>T NP_001341555.1:p.Asp379Val missense NM_001354627.2:c.1136A>T NP_001341556.1:p.Asp379Val missense NM_001354628.2:c.2117A>T NP_001341557.1:p.Asp706Val missense NM_001354629.2:c.2111A>T NP_001341558.1:p.Asp704Val missense NM_001354630.2:c.2045A>T NP_001341559.1:p.Asp682Val missense NC_000003.12:g.37050592A>T NC_000003.11:g.37092083A>T NG_007109.2:g.62243A>T LRG_216:g.62243A>T LRG_216t1:c.2210A>T LRG_216p1:p.Asp737Val - Protein change
- D737V, D396V, D639V, D668V, D704V, D379V, D496V, D706V, D682V
- Other names
- p.D737V:GAT>GTT
- Canonical SPDI
- NC_000003.12:37050591:A:T
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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
Trans-Omics for Precision Medicine (TOPMed) 0.00001
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
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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
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 |
5683 | 5744 |
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 (2) |
criteria provided, multiple submitters, no conflicts
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Feb 16, 2024 | RCV000115474.27 | |
Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Mar 23, 2023 | RCV000563079.13 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 5, 2024 | RCV000791373.7 | |
MLH1-related disorder
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Uncertain significance (1) |
criteria provided, single submitter
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Jan 11, 2024 | RCV003894921.1 |
Likely benign (1) |
criteria provided, single submitter
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Dec 1, 2023 | RCV003997127.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 15, 2024 | RCV004566929.1 |
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
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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
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
(Jan 05, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000254367.7
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 737 of the MLH1 protein … (more)
This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 737 of the MLH1 protein (p.Asp737Val). This variant is present in population databases (rs267607885, gnomAD 0.0009%). This missense change has been observed to co-occur in individuals with a different variant in MLH1 that has been determined to be pathogenic (PMID: 16341550), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 90090). 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. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 31784484). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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
(Feb 15, 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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Baylor Genetics
Accession: SCV005057982.1
First in ClinVar: Jun 17, 2024 Last updated: Jun 17, 2024 |
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Likely benign
(Mar 23, 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: SCV000684805.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
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Uncertain significance
(Jan 11, 2024)
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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: SCV004714834.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The MLH1 c.2210A>T variant is predicted to result in the amino acid substitution p.Asp737Val. This variant was reported, along with additional MLH1 variants, in individuals … (more)
The MLH1 c.2210A>T variant is predicted to result in the amino acid substitution p.Asp737Val. This variant was reported, along with additional MLH1 variants, in individuals with non-polyposis colorectal cancer (Pagenstecher et al. 2006. PubMed ID: 16341550; Mangold et al. 2005. PubMed ID: 15849733). The significance of these reports is unclear given the uncertainty of the clinical significance of the additional variants and/or the variant phasing. This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In ClinVar, this variant has conflicting interpretations of likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/90090/). 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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Likely Benign
(Dec 01, 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: SCV004843297.1
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 valine at codon 737 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
This missense variant replaces aspartic acid with valine at codon 737 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 been reported in a HNPCC family who also had a pathogenic splice mutation in the same gene, in which the c.2210A>T variant is stated to not segregate with disease (PMID: 15849733, 16341550, 21404117). This variant has been identified in 1/251274 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: 5
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Likely benign
(May 03, 2018)
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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: SCV000662010.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Aug 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001500307.21
First in ClinVar: Mar 14, 2021 Last updated: Aug 04, 2024 |
Number of individuals with the variant: 1
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Uncertain significance
(Feb 16, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000149383.15
First in ClinVar: May 17, 2014 Last updated: Sep 16, 2024 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: shown to be non-pathogenic via oligonucleotide-directed mutation screening (PMID: 31784484); Observed in trans with a MLH1 pathogenic variant in an individual meeting Amsterdam criteria; however, the variant was shown to not segregate with disease (PMID: 15849733, 16341550); This variant is associated with the following publications: (PMID: 9419403, 22949387, 18383312, 15849733, 21404117, 16341550, 23760103, 23435383, 20533529, 22753075, 12799449, 31784484) (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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Three-step site-directed mutagenesis screen identifies pathogenic MLH1 variants associated with Lynch syndrome. | Houlleberghs H | Journal of medical genetics | 2020 | PMID: 31784484 |
Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies. | Hardt K | Familial cancer | 2011 | PMID: 21404117 |
Aberrant splicing in MLH1 and MSH2 due to exonic and intronic variants. | Pagenstecher C | Human genetics | 2006 | PMID: 16341550 |
Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer. | Mangold E | International journal of cancer | 2005 | PMID: 15849733 |
Text-mined citations for rs267607885 ...
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.