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NM_000249.4(MLH1):c.595G>C (p.Glu199Gln)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(2);Uncertain significance(3)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Sep 29, 2021)
Last evaluated:
Oct 28, 2020
Accession:
VCV000090293.10
Variation ID:
90293
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.595G>C (p.Glu199Gln)

Allele ID
95767
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 37012017 (GRCh38) GRCh38 UCSC
3: 37053508 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000003.11:g.37053508G>C
NM_000249.3:c.595G>C NP_000240.1:p.Glu199Gln missense
NC_000003.12:g.37012017G>C
... more HGVS
Protein change
E199Q, E166Q, E101Q
Other names
-
Canonical SPDI
NC_000003.12:37012016:G:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00003
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00015
Links
ClinGen: CA011204
dbSNP: rs63749887
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely benign 1 criteria provided, single submitter Feb 14, 2020 RCV000218794.3
Uncertain significance 1 criteria provided, single submitter Oct 28, 2020 RCV000627702.4
Uncertain significance 1 criteria provided, single submitter May 11, 2018 RCV000663260.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Feb 9, 2019 RCV000165198.7
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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
Likely benign
(Feb 02, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000215910.5
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (2)
Comment:
No disease association in appropriately sized case-control study(ies);Other data supporting benign classification
Uncertain significance
(May 11, 2018)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome II
Allele origin: unknown
Counsyl
Accession: SCV000786488.2
Submitted: (Jun 20, 2018)
Evidence details
Publications
PubMed (4)
Uncertain significance
(Feb 09, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000684851.3
Submitted: (May 19, 2020)
Evidence details
Uncertain significance
(Oct 28, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colorectal neoplasms
Allele origin: germline
Invitae
Accession: SCV000543610.6
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (3)
Comment:
This sequence change replaces glutamic acid with glutamine at codon 199 of the MLH1 protein (p.Glu199Gln). The glutamic acid residue is moderately conserved and there … (more)
Likely benign
(Feb 14, 2020)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000279076.10
Submitted: (Sep 29, 2021)
Evidence details
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 17510385, 10495924, 16995940, … (more)

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
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Kobayashi Y Genome medicine 2017 PMID: 28166811
Accurate classification of MLH1/MSH2 missense variants with multivariate analysis of protein polymorphisms-mismatch repair (MAPP-MMR). Chao EC Human mutation 2008 PMID: 18383312
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Takahashi M Cancer research 2007 PMID: 17510385
In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects. Lastella P BMC genomics 2006 PMID: 16995940
Structure and function of the N-terminal 40 kDa fragment of human PMS2: a monomeric GHL ATPase. Guarné A The EMBO journal 2001 PMID: 11574484
Various mutation screening techniques in the DNA mismatch repair genes hMSH2 and hMLH1. Wahlberg S Genetic testing 1999 PMID: 10495924

Text-mined citations for rs63749887...

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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 Oct 30, 2021