ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.1066G>C (p.Gly356Arg)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.1066G>C (p.Gly356Arg)
Variation ID: 234059 Accession: VCV000234059.32
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7670643 (GRCh38) [ NCBI UCSC ] 17: 7573961 (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 Apr 29, 2017 Oct 8, 2024 Sep 6, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.1066G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Gly356Arg missense NM_001126112.3:c.1066G>C NP_001119584.1:p.Gly356Arg missense NM_001126113.3:c.*85G>C 3 prime UTR NM_001126114.3:c.*173G>C 3 prime UTR NM_001126115.2:c.670G>C NP_001119587.1:p.Gly224Arg missense NM_001126116.2:c.*173G>C 3 prime UTR NM_001126117.2:c.*85G>C 3 prime UTR NM_001126118.2:c.949G>C NP_001119590.1:p.Gly317Arg missense NM_001276695.3:c.*85G>C 3 prime UTR NM_001276696.3:c.*173G>C 3 prime UTR NM_001276697.3:c.589G>C NP_001263626.1:p.Gly197Arg missense NM_001276698.3:c.*173G>C 3 prime UTR NM_001276699.3:c.*85G>C 3 prime UTR NM_001276760.3:c.949G>C NP_001263689.1:p.Gly317Arg missense NM_001276761.3:c.949G>C NP_001263690.1:p.Gly317Arg missense NC_000017.11:g.7670643C>G NC_000017.10:g.7573961C>G NG_017013.2:g.21908G>C LRG_321:g.21908G>C LRG_321t1:c.1066G>C LRG_321p1:p.Gly356Arg - Protein change
- G224R, G317R, G356R, G197R
- Other names
- NM_000546.5(TP53):c.1066G>C
- p.Gly356Arg
- Canonical SPDI
- NC_000017.11:7670642:C:G
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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
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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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 |
3365 | 3464 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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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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Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jul 26, 2023 | RCV000213405.14 | |
Likely benign (3) |
reviewed by expert panel
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Sep 6, 2024 | RCV000471717.17 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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Jun 13, 2023 | RCV000481680.7 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 23, 2018 | RCV000781911.3 | |
TP53-related disorder
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Likely benign (1) |
no assertion criteria provided
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Feb 16, 2022 | RCV003919893.2 |
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
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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
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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
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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 Benign
(Sep 06, 2024)
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reviewed by expert panel
Method: curation
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen TP53 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001949906.2 First in ClinVar: Oct 02, 2021 Last updated: Sep 16, 2024 |
Comment:
The NM_000546.6: c.1066G>C variant in TP53 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 356 (p.Gly356Arg). This variant … (more)
The NM_000546.6: c.1066G>C variant in TP53 is a missense variant predicted to cause substitution of glycine by arginine at amino acid 356 (p.Gly356Arg). This variant has been observed in 2-3 heterozygous unrelated females from the same data source with no personal history of cancer prior to age 60 years and no personal history of sarcoma at any age (BS2_Supporting; ClinVar SCV: SCV000278550.7). This variant has an allele frequency of 0.000005932 (7/1179982 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed functional transactivation and retained growth suppression activity indicating that this variant does not impact protein function (BS3; PMIDs: 12826609, 29979965, 30224644). Computational predictor scores (BayesDel = -0.3473; Align GVGD Class C0) are below the recommended thresholds (BayesDel ≤ -0.008 and an Align GVGD Class ≤ 55), evidence that does not predict a damaging effect on TP53 via protein change. SpliceAI predicts that the variant has no impact on splicing. (BP4_Moderate). In summary, this variant meets the criteria to be classified as Likely Benign for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: BS2_Supporting, PM2_Supporting, BS3, BP4_Moderate. (Bayesian Points: -6; VCEP specifications version 2.0; 9/6/2024) (less)
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Uncertain significance
(Feb 23, 2018)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000920315.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: TP53 c.1066G>C (p.Gly356Arg) results in a non-conservative amino acid change located in the p53, tetramerisation domain of the encoded protein sequence. Four of … (more)
Variant summary: TP53 c.1066G>C (p.Gly356Arg) results in a non-conservative amino acid change located in the p53, tetramerisation domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245622 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.1066G>C variant has been reported in the literature, but this report does not provide strong evidence about an association of the variant with Li-Fraumeni Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
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Uncertain significance
(Aug 24, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000569810.7
First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; … (more)
Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies suggest no damaging effect: classified as functional based on transactivation assays (Kato 2003); This variant is associated with the following publications: (PMID: 12826609, 14559903) (less)
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Uncertain significance
(Jul 26, 2023)
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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: SCV000691572.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces glycine with arginine at codon 356 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with arginine at codon 356 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown that this variant is functional in yeast transcriptional activation assays and human cell growth suppression assays (PMID: 12826609, 30224644). To our knowledge, this variant has not been reported in individuals affected with TP53-related disorders in the literature. This variant has been identified in 1/245622 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
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Uncertain significance
(Jan 24, 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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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000545298.11
First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 356 of the TP53 protein (p.Gly356Arg). … (more)
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 356 of the TP53 protein (p.Gly356Arg). This variant is present in population databases (rs766786605, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 234059). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. (less)
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Likely benign
(Jun 08, 2021)
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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: SCV000278550.7
First in ClinVar: May 29, 2016 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
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Uncertain significance
(Jun 13, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004221344.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
In the published literature, this variant has been reported in individuals at risk for Li-Fraumeni syndrome (PMID: 28861920 (2017)). The variant was found in a … (more)
In the published literature, this variant has been reported in individuals at risk for Li-Fraumeni syndrome (PMID: 28861920 (2017)). The variant was found in a healthy individual in a large breast cancer association study (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/TP53)). Experimental studies report the variant does not impact TP53 function (PMIDs: 30224644 (2018), 12826609 (2003)). The frequency of this variant in the general population, 0.000004 (1/250802 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
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Uncertain Significance
(Aug 15, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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All of Us Research Program, National Institutes of Health
Accession: SCV004823721.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
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Comment:
This missense variant replaces glycine with arginine at codon 356 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure … (more)
This missense variant replaces glycine with arginine at codon 356 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (IARC database; PMID: 12826609). This variant has been observed in a tumor sample from an individual affected with triple-negative breast cancer (PMID: 24356096). This variant has been identified in 1/245622 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. (less)
Number of individuals with the variant: 3
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Uncertain significance
(Aug 22, 2017)
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no assertion criteria provided
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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True Health Diagnostics
Accession: SCV000788222.1
First in ClinVar: Jul 27, 2018 Last updated: Jul 27, 2018 |
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Likely benign
(Feb 16, 2022)
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no assertion criteria provided
Method: clinical testing
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TP53-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004730558.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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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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Breast Cancer Risk Genes - Association Analysis in More than 113,000 Women. | Breast Cancer Association Consortium | The New England journal of medicine | 2021 | PMID: 33471991 |
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 |
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 |
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 |
Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. | Balko JM | Cancer discovery | 2014 | PMID: 24356096 |
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 |
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/5e0b5fcb-74ae-405b-ba9f-054ce7b5cd41 | - | - | - | - |
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Text-mined citations for rs766786605 ...
HelpRecord last updated Oct 08, 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.