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NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(4)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Sep 25, 2021)
Last evaluated:
Mar 4, 2021
Accession:
VCV000090090.14
Variation ID:
90090
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.2210A>T (p.Asp737Val)

Allele ID
95564
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 37050592 (GRCh38) GRCh38 UCSC
3: 37092083 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_216:g.62243A>T
LRG_216t1:c.2210A>T LRG_216p1:p.Asp737Val
NC_000003.11:g.37092083A>T
... more HGVS
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
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Links
ClinGen: CA009102
dbSNP: rs267607885
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Mar 4, 2021 RCV000115474.8
Uncertain significance 1 criteria provided, single submitter Aug 28, 2020 RCV000791373.3
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Feb 3, 2021 RCV000563079.6
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
MLH1 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
3503 3539

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Aug 28, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000254367.5
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (1)
Comment:
This sequence change replaces aspartic acid with valine at codon 737 of the MLH1 protein (p.Asp737Val). The aspartic acid residue is highly conserved and there … (more)
Uncertain significance
(Mar 04, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000149383.14
Submitted: (Sep 25, 2021)
Evidence details
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on … (more)
Likely benign
(May 03, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000662010.3
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (2)
Comment:
Co-occurence with mutation in same gene (phase unknown);Does not segregate with disease in family study (genes with incomplete penetrance);In silico models in agreement (deleterious) and/or … (more)
Uncertain significance
(Feb 03, 2021)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000684805.4
Submitted: (Jun 11, 2021)
Evidence details
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)
Uncertain significance
(Aug 01, 2020)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
CeGaT Praxis fuer Humangenetik Tuebingen
Accession: SCV001500307.3
Submitted: (Jul 04, 2021)
Evidence details

Functional evidence

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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 this variant

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Title Author Journal Year Link
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

Text-mined citations for rs267607885...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Dec 04, 2021