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NM_000546.6(TP53):c.1040C>A (p.Ala347Asp)

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Interpretation:
Likely pathogenic​

Review status:
reviewed by expert panel FDA Recognized Database
Submissions:
6 (Most recent: Jun 22, 2021)
Last evaluated:
Aug 28, 2019
Accession:
VCV000043587.9
Variation ID:
43587
Description:
single nucleotide variant
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NM_000546.6(TP53):c.1040C>A (p.Ala347Asp)

Allele ID
52756
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17p13.1
Genomic location
17: 7670669 (GRCh38) GRCh38 UCSC
17: 7573987 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000017.11:g.7670669G>T
NC_000017.10:g.7573987G>T
NM_000546.6:c.1040C>A MANE Select NP_000537.3:p.Ala347Asp missense
... more HGVS
Protein change
A215D, A308D, A347D, A188D
Other names
-
Canonical SPDI
NC_000017.11:7670668:G:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
-
Links
ClinGen: CA000022
dbSNP: rs397516434
Varsome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Likely pathogenic 2 reviewed by expert panel Aug 28, 2019 RCV000468537.4
Pathogenic/Likely pathogenic 2 criteria provided, multiple submitters, no conflicts Mar 19, 2021 RCV000255021.4
Likely pathogenic 1 criteria provided, single submitter May 11, 2020 RCV000492626.2
Uncertain significance 1 no assertion criteria provided Jul 21, 2008 RCV000036529.2
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
TP53 Sufficient evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
2197 2260

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Likely pathogenic
(Aug 28, 2019)
reviewed by expert panel
Method: curation
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Allele origin: germline
ClinGen TP53 Variant Curation Expert Panel,ClinGen
FDA Recognized Database
Accession: SCV001142526.1
Submitted: (Sep 23, 2019)
Evidence details
Publications
PubMed (2)
Other databases
https://erepo.clinicalgenome.org…
Comment:
This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show a low functioning allele according to Kato, et al. and there is … (more)
Likely pathogenic
(May 11, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000581153.4
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (4)
Comment:
The p.A347D variant (also known as c.1040C>A), located in coding exon 9 of the TP53 gene, results from a C to A substitution at nucleotide … (more)
Uncertain significance
(Jun 11, 2019)
criteria provided, single submitter
Method: clinical testing
Li-Fraumeni syndrome
Allele origin: germline
Invitae
Accession: SCV000545289.4
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change replaces alanine with aspartic acid at codon 347 of the TP53 protein (p.Ala347Asp). The alanine residue is highly conserved and there is … (more)
Likely pathogenic
(Mar 29, 2017)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000602259.1
Submitted: (Aug 01, 2017)
Evidence details
Publications
PubMed (6)
Pathogenic
(Mar 19, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000321974.8
Submitted: (Jun 22, 2021)
Evidence details
Comment:
Published functional studies demonstrate a damaging effect: loss of tetramer formation, non-functional transactivation, and reduced growth suppression activity (Kato 2003, Kawaguchi 2005, Fischer 2018) Identified … (more)
Uncertain significance
(Jul 21, 2008)
no assertion criteria provided
Method: clinical testing
not specified
Allele origin: germline
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine
Accession: SCV000060184.5
Submitted: (Mar 21, 2019)
Evidence details
Publications
PubMed (2)

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
p53 Proteoforms and Intrinsic Disorder: An Illustration of the Protein Structure-Function Continuum Concept. Uversky VN International journal of molecular sciences 2016 PMID: 27834926
Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Villani A The Lancet. Oncology 2016 PMID: 27501770
Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Mai PL Cancer 2016 PMID: 27496084
Tetramer formation of tumor suppressor protein p53: Structure, function, and applications. Kamada R Biopolymers 2016 PMID: 26572807
Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. Abegglen LM JAMA 2015 PMID: 26447779
Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. Petitjean A Human mutation 2007 PMID: 17311302
The relationship among p53 oligomer formation, structure and transcriptional activity using a comprehensive missense mutation library. Kawaguchi T Oncogene 2005 PMID: 16007150
Understanding the function-structure and function-mutation relationships of p53 tumor suppressor protein by high-resolution missense mutation analysis. Kato S Proceedings of the National Academy of Sciences of the United States of America 2003 PMID: 12826609
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/d4905d59-9322-441b-9ed0-ea2304d97a65 - - - -

Text-mined citations for rs397516434...

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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 Aug 17, 2021