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NM_000249.4(MLH1):c.1652A>C (p.Asn551Thr)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(1);Uncertain significance(1)

Review status:
criteria provided, conflicting interpretations
Submissions:
2 (Most recent: Nov 30, 2020)
Last evaluated:
Jun 17, 2019
Accession:
VCV000089819.4
Variation ID:
89819
Description:
single nucleotide variant
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NM_000249.4(MLH1):c.1652A>C (p.Asn551Thr)

Allele ID
95293
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
3p22.2
Genomic location
3: 37040279 (GRCh38) GRCh38 UCSC
3: 37081770 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_216:g.51930A>C
LRG_216t1:c.1652A>C LRG_216p1:p.Asn551Thr
P40692:p.Asn551Thr
... more HGVS
Protein change
N551T, N210T, N310T, N518T, N193T, N453T
Other names
-
Canonical SPDI
NC_000003.12:37040278:A:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA006238
UniProtKB: P40692#VAR_012922
dbSNP: rs63750271
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Jun 17, 2019 RCV001012577.2
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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
(Jun 17, 2019)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV001344558.1
Submitted: (May 19, 2020)
Evidence details
Likely pathogenic
(Sep 25, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV001173046.2
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (12)
Comment:
The p.N551T variant (also known as c.1652A>C), located in coding exon 14 of the MLH1 gene, results from an A to C substitution at nucleotide … (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
Prevalence of Lynch syndrome in a Middle Eastern population with colorectal cancer. Siraj AK Cancer 2015 PMID: 25712738
The mutational spectrum of Lynch syndrome in cyprus. Loizidou MA PloS one 2014 PMID: 25133505
Expression defect size among unclassified MLH1 variants determines pathogenicity in Lynch syndrome diagnosis. Hinrichsen I Clinical cancer research : an official journal of the American Association for Cancer Research 2013 PMID: 23403630
Comprehensive functional assessment of MLH1 variants of unknown significance. Borràs E Human mutation 2012 PMID: 22736432
Identification of Lynch syndrome mutations in the MLH1-PMS2 interface that disturb dimerization and mismatch repair. Kosinski J Human mutation 2010 PMID: 20533529
A large fraction of unclassified variants of the mismatch repair genes MLH1 and MSH2 is associated with splicing defects. Tournier I Human mutation 2008 PMID: 18561205
Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Takahashi M Cancer research 2007 PMID: 17510385
Systematic mRNA analysis for the effect of MLH1 and MSH2 missense and silent mutations on aberrant splicing. Auclair J Human mutation 2006 PMID: 16395668
Differential rates of frameshift alterations in four repeat sequences of hereditary nonpolyposis colorectal cancer tumors. Paoloni-Giacobino A Human genetics 2002 PMID: 12215842
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
Excess of hMLH1 germline mutations in Swiss families with hereditary non-polyposis colorectal cancer. Hutter P International journal of cancer 1998 PMID: 9833759
Germline hMSH2 and hMLH1 gene mutations in incomplete HNPCC families. Wang Q International journal of cancer 1997 PMID: 9399661

Text-mined citations for rs63750271...

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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