ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1009C>T (p.Arg337Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.1009C>T (p.Arg337Cys)
Variation ID: 142536 Accession: VCV000142536.40
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670700 (GRCh38) [ NCBI UCSC ] 17: 7574018 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 19, 2017 Feb 28, 2024 Jan 8, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1009C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg337Cys missense NM_001126112.3:c.1009C>T NP_001119584.1:p.Arg337Cys missense NM_001126113.3:c.*28C>T 3 prime UTR NM_001126114.3:c.*116C>T 3 prime UTR NM_001126115.2:c.613C>T NP_001119587.1:p.Arg205Cys missense NM_001126116.2:c.*116C>T 3 prime UTR NM_001126117.2:c.*28C>T 3 prime UTR NM_001126118.2:c.892C>T NP_001119590.1:p.Arg298Cys missense NM_001276695.3:c.*28C>T 3 prime UTR NM_001276696.3:c.*116C>T 3 prime UTR NM_001276697.3:c.532C>T NP_001263626.1:p.Arg178Cys missense NM_001276698.3:c.*116C>T 3 prime UTR NM_001276699.3:c.*28C>T 3 prime UTR NM_001276760.3:c.892C>T NP_001263689.1:p.Arg298Cys missense NM_001276761.3:c.892C>T NP_001263690.1:p.Arg298Cys missense NC_000017.11:g.7670700G>A NC_000017.10:g.7574018G>A NG_017013.2:g.21851C>T LRG_321:g.21851C>T LRG_321t1:c.1009C>T LRG_321p1:p.Arg337Cys P04637:p.Arg337Cys - Protein change
- R205C, R298C, R337C, R178C
- Other names
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- Canonical SPDI
- NC_000017.11:7670699:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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TP53 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3196 | 3291 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV000131726.12 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Jan 8, 2024 | RCV000475086.10 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785479.4 | |
Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jun 18, 2022 | RCV001310211.5 | |
Pathogenic (1) |
criteria provided, single submitter
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Oct 11, 2019 | RCV001781474.6 | |
Pathogenic (1) |
criteria provided, single submitter
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Aug 11, 2023 | RCV003467184.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Apr 02, 2020)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
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Department of Molecular Diagnostics, Institute of Oncology Ljubljana
Accession: SCV001499817.1
First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
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Likely pathogenic
(Oct 19, 2020)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV001354213.2
First in ClinVar: Mar 25, 2020 Last updated: Jun 19, 2021 |
Comment:
This missense variant replaces arginine with cysteine at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction suggests that this variant may … (more)
This missense variant replaces arginine with cysteine at codon 337 in the tetramerization domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant causes a partial loss of transactivation function of TP53 protein in yeast (PMID: 9150393, 12826609, 14559903, 20407015, 21343334) and mammalian cells (PMID: 9766574, 10653977, 19454241, 20128691, 20505364). This variant has been reported in individuals diagnosed with classic or Chompret Li-Fraumeni syndrome (PMID 9150393, 9452042, 18511570, 20478780) and in an individual with early-onset breast cancer (PMID: 29752822) This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg337His, have been reported as disease-causing (ClinVar variation ID: 12379), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Pathogenic. (less)
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Likely pathogenic
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002582336.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Likely pathogenic
(Jun 18, 2022)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002582997.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Pathogenic
(May 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186766.8
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
The p.R337C pathogenic mutation (also known as c.1009C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at … (more)
The p.R337C pathogenic mutation (also known as c.1009C>T), located in coding exon 9 of the TP53 gene, results from a C to T substitution at nucleotide position 1009. The arginine at codon 337 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with TP53-related disease (Ambry internal data). In addition, this variant has been detected in several individuals at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant in the tetramerization domain is reported as non-functional in yeast based assays of transactivation (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). A study conducted in human cell lines indicates that this alteration is deficient at growth suppression but has no dominant negative effect (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
Number of individuals with the variant: 1
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Pathogenic
(Feb 03, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844983.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: TP53 c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Four … (more)
Variant summary: TP53 c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change located in the p53, tetramerisation domain (IPR010991) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250834 control chromosomes (gnomAD). c.1009C>T has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (e.g. Renaux-Petel_2017, Fischer_2018, Frone_2021). These data indicate that the variant is very likely to be associated with disease. Multiple publications report experimental evidence evaluating an impact on protein function (e.g. Lomax_1997, Kato_2003, Imagawa_2009, Fischer_2018). These studies indicate that the variant results in a substantial decrease in transcriptional activity compared to the WT protein and a reduction in tumor suppression functions including increased colony formation, decreased growth arrest, and impaired apoptotic response. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as pathogenic (n=3)/likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Aug 11, 2023)
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criteria provided, single submitter
Method: clinical testing
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Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004206244.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Oct 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002022394.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000545330.8
First in ClinVar: Apr 17, 2017 Last updated: Feb 28, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 337 of the TP53 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 337 of the TP53 protein (p.Arg337Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni like syndrome (PMID: 9150393, 9452042, 17606709, 18511570, 20478780). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142536). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 9150393, 9704930, 9704931, 12826609, 20128691, 21343334). This variant disrupts the p.Arg337 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9704930, 10864200, 12826609, 16033918, 20407015). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Aug 26, 2022)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
unknown
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BRCAlab, Lund University
Accession: SCV002589039.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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Likely pathogenic
(Dec 01, 2018)
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no assertion criteria provided
Method: research
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Neoplasm of ovary
Affected status: yes
Allele origin:
somatic
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German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000924051.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
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not provided
(-)
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no classification provided
Method: phenotyping only
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Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
unknown
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GenomeConnect - Invitae Patient Insights Network
Accession: SCV004228479.1
First in ClinVar: Jan 26, 2024 Last updated: Jan 26, 2024 |
Comment:
Variant interpreted as Pathogenic and reported on 02-19-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the … (more)
Variant interpreted as Pathogenic and reported on 02-19-2015 by Lab Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. (less)
Clinical Features:
Maternal teratogenic exposure (present)
Indication for testing: Diagnostic
Age: 20-29 years
Sex: female
Method: Gene Panel Sequencing
Testing laboratory: Ambry Genetics
Date variant was reported to submitter: 2015-02-19
Testing laboratory interpretation: Pathogenic
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Suspected clonal hematopoiesis as a natural functional assay of TP53 germline variant pathogenicity. | Fortuno C | Genetics in medicine : official journal of the American College of Medical Genetics | 2022 | PMID: 34906512 |
Quantification of Discordant Variant Interpretations in a Large Family-Based Study of Li-Fraumeni Syndrome. | Frone MN | JCO precision oncology | 2021 | PMID: 34805717 |
Germline mutations in 40 cancer susceptibility genes among Chinese patients with high hereditary risk breast cancer. | Li JY | International journal of cancer | 2019 | PMID: 29752822 |
The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
Association Between the Oligomeric Status of p53 and Clinical Outcomes in Li-Fraumeni Syndrome. | Fischer NW | Journal of the National Cancer Institute | 2018 | PMID: 29955864 |
Contribution of de novo and mosaic TP53 mutations to Li-Fraumeni syndrome. | Renaux-Petel M | Journal of medical genetics | 2018 | PMID: 29070607 |
Higher-than-expected population prevalence of potentially pathogenic germline TP53 variants in individuals unselected for cancer history. | de Andrade KC | Human mutation | 2017 | PMID: 28861920 |
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
Specific TP53 Mutants Overrepresented in Ovarian Cancer Impact CNV, TP53 Activity, Responses to Nutlin-3a, and Cell Survival. | Mullany LK | Neoplasia (New York, N.Y.) | 2015 | PMID: 26585234 |
TP53 mutations in de novo acute myeloid leukemia patients: longitudinal follow-ups show the mutation is stable during disease evolution. | Hou HA | Blood cancer journal | 2015 | PMID: 26230955 |
TP53 mutation characteristics in therapy-related myelodysplastic syndromes and acute myeloid leukemia is similar to de novo diseases. | Ok CY | Journal of hematology & oncology | 2015 | PMID: 25952993 |
Functional characterisation of p53 mutants identified in breast cancers with suboptimal responses to anthracyclines or mitomycin. | Berge EO | Biochimica et biophysica acta | 2013 | PMID: 23246812 |
A novel hierarchical prognostic model of AML solely based on molecular mutations. | Grossmann V | Blood | 2012 | PMID: 22915647 |
TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. | Rücker FG | Blood | 2012 | PMID: 22186996 |
TP53 mutations in low-risk myelodysplastic syndromes with del(5q) predict disease progression. | Jädersten M | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2011 | PMID: 21519010 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
[Li Fraumeni syndrome: a case with multiple primary cancers and presenting a germline p53 mutation]. | Landolsi S | Annales de biologie clinique | 2010 | PMID: 20478780 |
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
Evaluation of transcriptional activity of p53 in individual living mammalian cells. | Imagawa T | Analytical biochemistry | 2009 | PMID: 19454241 |
Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. | Bougeard G | Journal of medical genetics | 2008 | PMID: 18511570 |
Transcriptional functionality of germ line p53 mutants influences cancer phenotype. | Monti P | Clinical cancer research : an official journal of the American Association for Cancer Research | 2007 | PMID: 17606709 |
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
Penetrance of adrenocortical tumours associated with the germline TP53 R337H mutation. | Figueiredo BC | Journal of medical genetics | 2006 | PMID: 16033918 |
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 |
A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
P53 germline mutations in childhood cancers and cancer risk for carrier individuals. | Chompret A | British journal of cancer | 2000 | PMID: 10864200 |
Characterization of the oligomerization defects of two p53 mutants found in families with Li-Fraumeni and Li-Fraumeni-like syndrome. | Davison TS | Oncogene | 1998 | PMID: 9704931 |
Characterization of p53 oligomerization domain mutations isolated from Li-Fraumeni and Li-Fraumeni like family members. | Lomax ME | Oncogene | 1998 | PMID: 9704930 |
A germline missense mutation R337C in exon 10 of the human p53 gene. | Luca JW | Human mutation | 1998 | PMID: 9452042 |
Two functional assays employed to detect an unusual mutation in the oligomerisation domain of p53 in a Li-Fraumeni like family. | Lomax ME | Oncogene | 1997 | PMID: 9150393 |
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Text-mined citations for rs587782529 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.