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NM_000249.4(MLH1):c.187G>A (p.Asp63Asn)

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Interpretation:
Pathogenic/Likely pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
5 (Most recent: Nov 30, 2020)
Last evaluated:
Feb 5, 2020
Accession:
VCV000089920.8
Variation ID:
89920
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.187G>A (p.Asp63Asn)

Allele ID
95394
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 36996689 (GRCh38) GRCh38 UCSC
3: 37038180 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NM_000249.3:c.187G>A NP_000240.1:p.Asp63Asn missense
LRG_216:g.8340G>A
LRG_216t1:c.187G>A LRG_216p1:p.Asp63Asn
... more HGVS
Protein change
D63N
Other names
p.D63N:GAC>AAC
Canonical SPDI
NC_000003.12:36996688:G:A
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA007334
dbSNP: rs63750850
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Feb 5, 2020 RCV000160535.7
Likely pathogenic 1 criteria provided, single submitter Feb 26, 2019 RCV000075399.5
Likely pathogenic 1 criteria provided, single submitter Sep 29, 2016 RCV000212515.3
Likely pathogenic 1 criteria provided, single submitter Mar 12, 2018 RCV000694220.1
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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 pathogenic
(Sep 29, 2016)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000211107.9
Submitted: (Jan 29, 2019)
Evidence details
Comment:
This variant is denoted MLH1 c.187G>A at the cDNA level, p.Asp63Asn (D63N) at the protein level, and results in the change of an Aspartic Acid … (more)
Pathogenic
(May 14, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000215751.5
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (3)
Comment:
The p.D63N pathogenic mutation (also known as c.187G>A), located in coding exon 2 of the MLH1 gene, results from a G to A substitution at … (more)
Likely pathogenic
(Mar 12, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary nonpolyposis colon cancer
Allele origin: germline
Invitae
Accession: SCV000822654.1
Submitted: (Aug 29, 2018)
Evidence details
Publications
PubMed (6)
Comment:
This sequence change replaces aspartic acid with asparagine at codon 63 of the MLH1 protein (p.Asp63Asn). The aspartic acid residue is highly conserved and there … (more)
Likely pathogenic
(Feb 26, 2019)
criteria provided, single submitter
Method: clinical testing
Lynch syndrome
Allele origin: germline
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000696133.3
Submitted: (Sep 24, 2019)
Evidence details
Publications
PubMed (3)
Comment:
Variant summary: MLH1 c.187G>A (p.Asp63Asn) results in a conservative amino acid change located in the Histidine kinase/HSP90-like ATPase domain of the encoded protein sequence. Four … (more)
Likely pathogenic
(Feb 05, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV001340137.1
Submitted: (May 19, 2020)
Comment:
This missense variant replaces aspartic acid with asparagine at codon 63 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact … (more)
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
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Evaluation of CADD Scores in Curated Mismatch Repair Gene Variants Yields a Model for Clinical Validation and Prioritization. van der Velde KJ Human mutation 2015 PMID: 25871441
Verification of the three-step model in assessing the pathogenicity of mismatch repair gene variants. Kansikas M Human mutation 2011 PMID: 21120944
Functional analysis helps to clarify the clinical importance of unclassified variants in DNA mismatch repair genes. Ou J Human mutation 2007 PMID: 17594722
Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing. Papp J World journal of gastroenterology 2007 PMID: 17569143
Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1. Raevaara TE Gastroenterology 2005 PMID: 16083711
Mutations within the hMLH1 and hPMS2 subunits of the human MutLalpha mismatch repair factor affect its ATPase activity, but not its ability to interact with hMutSalpha. Räschle M The Journal of biological chemistry 2002 PMID: 11948175

Text-mined citations for rs63750850...

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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 24, 2021