ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.524G>A (p.Arg175His)
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
No data submitted for somatic clinical impact
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
The aggregate oncogenicity classification for this variant for one or more tumor types, using the ClinGen/CGC/VICC terminology. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.524G>A (p.Arg175His)
Variation ID: 12374 Accession: VCV000012374.76
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675088 (GRCh38) [ NCBI UCSC ] 17: 7578406 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Oct 19, 2014 Jun 29, 2025 Sep 6, 2024 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_000546.6:c.524G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg175His missense NM_001126112.3:c.524G>A NP_001119584.1:p.Arg175His missense NM_001126113.3:c.524G>A NP_001119585.1:p.Arg175His missense NM_001126114.1:c.524G>A NM_001126114.3:c.524G>A NP_001119586.1:p.Arg175His missense NM_001126115.2:c.128G>A NP_001119587.1:p.Arg43His missense NM_001126116.2:c.128G>A NP_001119588.1:p.Arg43His missense NM_001126117.2:c.128G>A NP_001119589.1:p.Arg43His missense NM_001126118.2:c.407G>A NP_001119590.1:p.Arg136His missense NM_001276695.3:c.407G>A NP_001263624.1:p.Arg136His missense NM_001276696.3:c.407G>A NP_001263625.1:p.Arg136His missense NM_001276697.3:c.47G>A NP_001263626.1:p.Arg16His missense NM_001276698.3:c.47G>A NP_001263627.1:p.Arg16His missense NM_001276699.3:c.47G>A NP_001263628.1:p.Arg16His missense NM_001276760.3:c.407G>A NP_001263689.1:p.Arg136His missense NM_001276761.3:c.407G>A NP_001263690.1:p.Arg136His missense NC_000017.11:g.7675088C>T NC_000017.10:g.7578406C>T NG_017013.2:g.17463G>A LRG_321:g.17463G>A LRG_321t1:c.524G>A LRG_321p1:p.Arg175His P04637:p.Arg175His - Protein change
- R175H, R136H, R43H, R16H
- Other names
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p.R175H:CGC>CAC
NM_000546.6(TP53):c.524G>A
- Canonical SPDI
- NC_000017.11:7675087:C:T
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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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variation affecting protein function; Variation Ontology [VariO:0003]
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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.
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The Genome Aggregation Database (gnomAD), exomes 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
- Links
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
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
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 |
3584 | 3685 |
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 (8) |
criteria provided, multiple submitters, no conflicts
|
Nov 12, 2024 | RCV000013173.42 | |
Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Dec 9, 2024 | RCV000131301.25 | |
Pathogenic (6) |
reviewed by expert panel
|
Sep 6, 2024 | RCV000204931.33 | |
Pathogenic (8) |
criteria provided, multiple submitters, no conflicts
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Mar 4, 2025 | RCV000213054.29 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 29, 2016 | RCV000239398.10 | |
Pathogenic (1) |
no assertion criteria provided
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Jul 1, 2021 | RCV003162247.8 | |
Likely pathogenic (1) |
no assertion criteria provided
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Dec 1, 2018 | RCV000785352.10 | |
Pathogenic (1) |
no assertion criteria provided
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Apr 30, 2019 | RCV001255668.9 | |
Pathogenic (1) |
criteria provided, single submitter
|
- | RCV001270268.10 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 19, 2021 | RCV001527463.11 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV001270269.10 | |
TP53-related disorder
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Pathogenic (1) |
criteria provided, single submitter
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May 1, 2024 | RCV004797760.1 |
Pathogenic (1) |
criteria provided, single submitter
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Apr 10, 2022 | RCV002476956.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 28, 2024 | RCV003466854.2 | |
click to load more conditions click to collapse |
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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Pathogenic
(Sep 06, 2024)
C
Contributing to aggregate classification
|
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: SCV005201131.1 First in ClinVar: Sep 16, 2024 Last updated: Sep 16, 2024 |
Comment:
The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant … (more)
The NM_000546.6: c.524G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 175 (p.Arg175His). This variant has been reported in 3 unrelated families meeting Classic and Revised Chompret criteria.Based on this evidence, this variant scores 2.5 total points meeting the TP53 VCEP phenotype scoring criteria of 2-3.5 points. (PS4_Moderate: 8825920, 11370630, 8164043). The variant has been reported to segregate with LFS-associated cancers in 5-6 meioses in 1 family (PP1_Moderate; PMID: 8825920). In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant resides within a codon (NM_00546.4: 175, 245, 248, 249, 273, 282) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157). Computational predictor scores (BayesDel = 0.54619; Align GVGD = Class C25) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of > 15), evidence that correlates with impact to TP53 via protein change (PP3). This variant has an allele frequency of 0.000005932 (7/1180032 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 summary, this variant meets the criteria to be classified as [CLASSIFICATION] for Li Fraumeni syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS3, PP1_Moderate, PM1, PS4_Moderate, PP3, PM2_Supporting. (Bayesian Points: 12; VCEP specifications version 2.0; 9/6/2024) (less)
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Pathogenic
(Apr 17, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000806241.1
First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018 |
|
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Pathogenic
(Jul 24, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731790.2
First in ClinVar: Apr 09, 2018 Last updated: Aug 26, 2019 |
Comment:
The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 … (more)
The p.Arg175His variant in TP53 has been reported in >16 individuals with Li-Fra umeni syndrome, and segregated with disease in 3 affected relatives from 1 famil y (McIntyre 1994, Varley 1997, Wong 2006, Bougeard 2008, Walsh 2011, Melhem-Bert randt 2012, Park 2016). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID# 12374). In vitro functional studies provide some evidence that the p.Arg175His variant may impact protein function (Kogan-S akin 2011, Grugan 2013) and an in-vivo mouse model has shown that this variant c auses TP53-related tumors (Liu 2010). Additionally, the p.Arg175His variant has been identified in 1/111550 European chromosomes by gnomAD (http://gnomad.broadi nstitute.org). Computational prediction tools and conservation analysis suggest that the p.Arg175His variant may impact the protein and 3 other amino acid chang es at this position (Leu, Gly, Cys) have been associated with Li-Fraumeni syndro me (HGMD database; Stenson 2017). In summary, this variant meets criteria to be classified as pathogenic for Li-Fraumeni syndrome in an autosomal dominant manne r based on segregation studies, increased prevalence in affected individuals, ve ry low frequency in controls and functional evidence. ACMG/AMP Criteria applied: PS4, PP1, PS3, PM2. (less)
Number of individuals with the variant: 4
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Pathogenic
(Apr 10, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Familial cancer of breast
Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Familial pancreatic carcinoma Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000894156.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
|
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Pathogenic
(Nov 03, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011128.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
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Pathogenic
(May 11, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004044216.2
First in ClinVar: Oct 21, 2023 Last updated: Oct 28, 2023 |
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:8825920, 8118819, 7887414]. Functional studies indicate … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID:8825920, 8118819, 7887414]. Functional studies indicate this variant impacts protein function [PMID: 14743206, 15607980]. This variant is expected to disrupt protein structure [PMID: 8023157, Myriad internal data]. (less)
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Pathogenic
(Sep 18, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004823789.1
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)
|
Comment:
This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces arginine with histidine at codon 175 in the DNA binding 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 results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Number of individuals with the variant: 1
Zygosity: Single Heterozygote
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Pathogenic
(Jan 07, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002074556.3
First in ClinVar: Feb 12, 2022 Last updated: May 12, 2024 |
Comment:
Variant summary: TP53 c.524G>A (p.Arg175His) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four … (more)
Variant summary: TP53 c.524G>A (p.Arg175His) results in a non-conservative amino acid change located in the p53, DNA-binding domain (IPR011615) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251276 control chromosomes. c.524G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome, including 2 families where the variant strongly segregated with disease (Varley_1995, Varley_1997, etc). These data indicate that the variant is very likely to be associated with disease. In vitro functional studies show that R175H results in decreased activation of Tp53 targets, and additionally confers a gain of function to Tp53, resulting in aberrant activation of gene transcription and enhanced cell migration (TP53 database, Yeudall_2012). Additional evidence from an animal model indicates that this variant contributes to a phenotype similar to tumorigenesis (including thymic tumors, sarcomas, peripheral lymphomas and germ-cell tumors) (Liu_2010). Ten ClinVar submitters have assessed this variant since 2014: all ten classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 01, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
TP53-related disorder
Affected status: yes
Allele origin:
somatic
|
Swedish National ChiCaP Initative, Genomic Medicine Sweden
Accession: SCV005419199.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
|
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Pathogenic
(Jan 10, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: yes
Allele origin:
germline
|
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet
Accession: SCV005685067.1
First in ClinVar: Feb 01, 2025 Last updated: Feb 01, 2025 |
Comment:
The following ACMG criteria was used: PS3, PP1_MOD, PM1, PS4_MOD, PP3, PM2_SUP
|
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Pathogenic
(Dec 15, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: research
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
Department of Pediatrics, Memorial Sloan Kettering Cancer Center
Accession: SCV001478188.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
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Pathogenic
(Jan 04, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000211798.12
First in ClinVar: Feb 24, 2015 Last updated: Jul 24, 2021 |
Comment:
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Monti et al., 2011; Wasserman et al., … (more)
Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato et al., 2003; Monti et al., 2011; Wasserman et al., 2015; Kotler et al., 2018); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31447099, 31105275, 15510160, 12826609, 19556618, 21343334, 25584008, 29979965, 8118819, 8164043, 10864200, 12200603, 16401470, 22233476, 28369373, 30577483, 30840781, 30093976, 29324801, 30092803, 30720243, 30709875, 28472496, 29753700, 29360550, 28975465, 29470806, 19127115, 29360161, 28818432, 29416795, 27153395, 12610779, 11494139, 11370630, 8308926, 7887414, 8099841, 23792586, 20689556, 15492269, 21426305, 22006311, 24573247, 22286061, 21305319, 17606709, 21761402, 24651015, 20128691, 24729566, 15170137, 29489754, 28861920, 28724667, 15607981, 15607980, 27516001, 27374712, 27714481, 27501770, 27323394, 23172776, 22265402, 21601526, 22851211, 21059199, 20501846, 18511570, 17308077, 16551709, 15951970) (less)
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Pathogenic
(Jun 18, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002582493.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
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Pathogenic
(Jun 18, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: no
Allele origin:
germline
|
Genome-Nilou Lab
Accession: SCV002583153.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
|
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Pathogenic
(Mar 28, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Adrenocortical carcinoma, hereditary
Affected status: unknown
Allele origin:
unknown
|
Baylor Genetics
Accession: SCV004206223.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
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Pathogenic
(Sep 19, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186273.10
First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025 |
Comment:
The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at … (more)
The p.R175H pathogenic mutation (also known as c.524G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 524. This changes the amino acid from an arginine to a histidine at codon 175. This mutation occurs at a well-characterized mutation hotspot (codon 175) in the critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including osteosarcomas, rhabdomyosarcomas, early onset colon cancer, breast cancer, and pediatric adrenal cortical tumors (McIntyre JF et al. J. Clin. Oncol. 1994 May;12(5):925-930; Varley JM et al. J. Med. Genet. 1995 Dec;32:942-945; Wong P et al. Gastroenterology. 2006 Jan;130:73-79; Hwang SM et al. Korean J. Lab Med. 2008 Dec;28(6):493-497; Melhem-Bertrandt A et al. Cancer. 2012 Feb;118(4):908-13; Choong SS et al. Clin. Genet. 2012 Dec;82(6):564-8; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Park KJ et al. Ann. Lab. Med. 2016 Sep;36:463-8; Dudley B et al. Cancer. 2018 Apr;124(8):1691-1700). This variant is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Dec 09, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Accession: SCV005688871.1
First in ClinVar: Feb 08, 2025 Last updated: Feb 08, 2025 |
Comment:
The missense variant NM_000546.6(TP53):c.524G>A (p.Arg175His) causes the same amino acid change as a previously established pathogenic variant. There is a small physicochemical difference between arginine … (more)
The missense variant NM_000546.6(TP53):c.524G>A (p.Arg175His) causes the same amino acid change as a previously established pathogenic variant. There is a small physicochemical difference between arginine and histidine, which is not likely to impact secondary protein structure as these residues share similar properties. The gene TP53 has a low rate of benign missense variation as indicated by a high missense variants Z-Score of 1.15. The p.Arg175His missense variant is predicted to be damaging by both SIFT and PolyPhen2. . The nucleotide c.524 in TP53 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic (less)
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Pathogenic
(Jan 25, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000261917.13
First in ClinVar: Jan 31, 2016 Last updated: Feb 25, 2025 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 175 of the TP53 protein (p.Arg175His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 175 of the TP53 protein (p.Arg175His). This variant is present in population databases (rs28934578, gnomAD 0.0009%). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 8164043, 8825920, 16401470, 21761402, 22006311). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12374). Invitae Evidence Modeling incorporating data from in vitro 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: 12007217, 12826609, 15607980, 15607981, 20516128, 23263379, 24573247, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. (less)
|
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Pathogenic
(Mar 04, 2025)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005872480.1
First in ClinVar: Mar 11, 2025 Last updated: Mar 11, 2025 |
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: case-control
|
Squamous cell carcinoma of the head and neck
Affected status: yes
Allele origin:
somatic
|
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo
Accession: SCV001450483.2
First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025 |
Age: 50-59 years
Sex: male
Geographic origin: Sri Lanka
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: case-control
|
Colorectal cancer
Affected status: yes
Allele origin:
somatic
|
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo
Accession: SCV001450484.2
First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025 |
Age: 60-69 years
Sex: male
Geographic origin: Sri Lanka
|
|
Pathogenic
(Nov 12, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
maternal
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV005368520.3
First in ClinVar: Oct 13, 2024 Last updated: Apr 13, 2025 |
Comment:
Criteria applied: PS3,PS4,PM1,PP3
Clinical Features:
Family history of cancer (present)
Sex: female
|
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Pathogenic
(Aug 05, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV000905051.4
First in ClinVar: May 19, 2019 Last updated: May 03, 2025 |
Comment:
This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant … (more)
This missense variant replaces arginine with histidine at codon 175 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have shown that this variant results in the loss of TP53 protein function (PMID: 12826609, 15607981, 23263379, 29979965, 30224644), causes chromosomal instability (PMID: 25059482), and promotes tumor cell invasion (PMID: 15607981, 23792586). In mouse models of Li-Fraumeni syndrome, this variant has also been shown to impair TP53 function and cause TP53-related tumors (PMID: 15607980, 15607981). This variant has been reported in individuals affected with Li-Fraumeni syndrome meeting classic or Chompret diagnostic criteria (PMID: 8164043 , 8825920, 16401470, 21761402, 23172776, 27374712, 27516001). This variant has been shown to segregate with disease in a 4-generation extended family affected with Li-Fraumeni syndrome (PMID: 8825920). This variant has been identified in 1/251276 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. (less)
Platform type: NGS
|
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Pathogenic
(Jul 24, 2014)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
|
Pathway Genomics
Accession: SCV000189994.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
|
Likely pathogenic
(Dec 01, 2018)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
Ovarian neoplasm
Affected status: yes
Allele origin:
somatic
|
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Accession: SCV000923920.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Platform type: next-gen sequencing
|
|
Pathogenic
(Apr 30, 2019)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
Lip and oral cavity carcinoma
Affected status: yes
Allele origin:
somatic
|
Institute of Medical Sciences, Banaras Hindu University
Accession: SCV001432233.1
First in ClinVar: Sep 18, 2020 Last updated: Sep 18, 2020 |
|
|
Pathogenic
(Mar 19, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Familial cancer of breast
Affected status: no
Allele origin:
somatic
|
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738476.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808819.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001959136.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(Jul 01, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: research
|
Gastric cancer
Affected status: unknown
Allele origin:
germline
|
Laboratory for Genotyping Development, RIKEN
Accession: SCV002758490.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
unknown
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000692083.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
|
Pathogenic
(Aug 01, 2005)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
LI-FRAUMENI SYNDROME 1
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000033420.4
First in ClinVar: Apr 04, 2013 Last updated: Jul 13, 2019 |
Comment on evidence:
Varley et al. (1995) studied an extensively affected 4-generation family with Li-Fraumeni syndrome-1 (151623). The structure of the family was sufficient to establish linkage to … (more)
Varley et al. (1995) studied an extensively affected 4-generation family with Li-Fraumeni syndrome-1 (151623). The structure of the family was sufficient to establish linkage to TP53. Subsequent DNA sequence analysis showed a CGC-to-CAC transition in exon 5 of the TP53 gene, resulting in an arg175-to-his (R175H) substitution that altered a recognition site for the restriction enzyme HhaI. This LFS family was unusual for the presence of 2 gastric carcinomas; endometrial cancers were absent, and malignancies were of early onset and particularly severe. Two persons developed a childhood sarcoma, and brain tumors were present in 4. An increase in the risk of breast cancer in mothers of children with osteosarcoma and chondrosarcoma had been reported and was a phenomenon not demonstrated in this family. By in vitro studies, Capponcelli et al. (2005) found that R175H fibroblasts showed increased resistance to doxorubicin treatment with decreased nuclear localization of the p53 protein compared with wildtype cells. (less)
|
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
None
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001551443.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TP53 p.Arg175His variant was identified in 14 of 2378 proband chromosomes (frequency: 0.006) from individuals or families with Li Fraumeni syndrome, breast, ovarian and/or … (more)
The TP53 p.Arg175His variant was identified in 14 of 2378 proband chromosomes (frequency: 0.006) from individuals or families with Li Fraumeni syndrome, breast, ovarian and/or colon cancer (Walsh 2011, Melhem-Bertrandt 2012, Wong 2006, Bougeard 2008, Damineni 2014). This variant has also been identified in a child diagnosed with adrenocortical carcinoma at 6 months of age (Choong 2012) and a family that includes two individuals diagnosed with childhood sarcomas and four individuals diagnosed with brain tumours (Varley 1995). The variant was identified in dbSNP and ClinVar (classified as pathogenic by GeneDx, Invitae, Ambry Genetics, and 8 other submitters) . The variant was identified in control databases in 1 of 251276 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European (non-Finnish) population in 1 of 113600 chromosomes (freq: 0.000009), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The R175 residue is a mutation hotspot and results in a structurally unstable, unfolded p53 protein (Xu 2014). The R175H variant has been shown to confer oncogenic gain of function to the p53 protein by multiple studies (Petitjean 2007, Capponcelli 2005), which is hypothesized to occur via the increased activation of the c-Met receptor tyrosine kinase and/or the inactivation of the ATM-dependent DNA damage response, resulting in a defective G2/M checkpoint (Grugan 2013, Liu 2010). The p.Arg175 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the His variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001906154.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021 |
|
|
Pathogenic
(Jul 29, 2016)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Esophageal cancer
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo
Accession: SCV000297733.2
First in ClinVar: Aug 13, 2016 Last updated: Apr 13, 2025 |
Comment:
SIFT:Deleterious (score: 0) MutationTaster:Disease causing (p-value: 1)
Age: 50-59 years
Sex: female
Ethnicity/Population group: Sri Lanka/Sinhalese
Geographic origin: Sri Lanka
Platform type: Sanger sequencing
|
|
Pathogenic
(Mar 18, 2016)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000488375.3
First in ClinVar: Sep 04, 2016 Last updated: Jun 29, 2025 |
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
|
|
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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variation affecting protein function
(VariO:0003)
|
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo
Accession: SCV000297733.2
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
Pattern of nucleotide variants of TP53 and their correlation with the expression of p53 and its downstream proteins in a Sri Lankan cohort of breast and colorectal cancer patients. | Manoharan V | BMC cancer | 2020 | PMID: 32000721 |
Nucleotide variants and protein expression of TP53 in a Sri Lankan cohort of patients with head and neck cancer. | Manoharan V | Molecular medicine reports | 2019 | PMID: 30816478 |
Hematologic malignancies and Li-Fraumeni syndrome. | Swaminathan M | Cold Spring Harbor molecular case studies | 2019 | PMID: 30709875 |
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 |
Clinical characteristics and registry-validated extended pedigrees of germline TP53 mutation carriers in Denmark. | Stoltze U | PloS one | 2018 | PMID: 29324801 |
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing. | Mandelker D | JAMA | 2017 | PMID: 28873162 |
The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. | Stenson PD | Human genetics | 2017 | PMID: 28349240 |
Multiple primary tumors in a family with Li-Fraumeni syndrome with a TP53 germline mutation identified by next-generation sequencing. | Zampiga V | The International journal of biological markers | 2016 | PMID: 27516001 |
Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome. | Park KJ | Annals of laboratory medicine | 2016 | PMID: 27374712 |
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
Different TP53 mutations are associated with specific chromosomal rearrangements, telomere length changes, and remodeling of the nuclear architecture of telomeres. | Samassekou O | Genes, chromosomes & cancer | 2014 | PMID: 25059482 |
Heterogeneity of Li-Fraumeni syndrome links to unequal gain-of-function effects of p53 mutations. | Xu J | Scientific reports | 2014 | PMID: 24573247 |
A common p53 mutation (R175H) activates c-Met receptor tyrosine kinase to enhance tumor cell invasion. | Grugan KD | Cancer biology & therapy | 2013 | PMID: 23792586 |
p53 mutations in cancer. | Muller PA | Nature cell biology | 2013 | PMID: 23263379 |
Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. | Zerdoumi Y | Human mutation | 2013 | PMID: 23172776 |
The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. | Leroy B | Nucleic acids research | 2013 | PMID: 23161690 |
Childhood adrenocortical carcinoma as a sentinel cancer for detecting families with germline TP53 mutations. | Choong SS | Clinical genetics | 2012 | PMID: 22233476 |
Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. | Walsh T | Proceedings of the National Academy of Sciences of the United States of America | 2011 | PMID: 22006311 |
Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
Joint effects of germ-line TP53 mutation, MDM2 SNP309, and gender on cancer risk in family studies of Li-Fraumeni syndrome. | Wu CC | Human genetics | 2011 | PMID: 21305319 |
Mutant p53(R175H) upregulates Twist1 expression and promotes epithelial-mesenchymal transition in immortalized prostate cells. | Kogan-Sakin I | Cell death and differentiation | 2011 | PMID: 20689556 |
The tumor suppressor p53: from structures to drug discovery. | Joerger AC | Cold Spring Harbor perspectives in biology | 2010 | PMID: 20516128 |
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 |
A common gain of function of p53 cancer mutants in inducing genetic instability. | Liu DP | Oncogene | 2010 | PMID: 19881536 |
Genetic counseling can influence the course of a suspected familial cancer syndrome patient: from a case of Li-Fraumeni like syndrome with a germline mutation in the TP53 gene. | Hwang SM | The Korean journal of laboratory medicine | 2008 | PMID: 19127115 |
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 |
Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. | Wong P | Gastroenterology | 2006 | PMID: 16401470 |
Evaluation of the molecular mechanisms involved in the gain of function of a Li-Fraumeni TP53 mutation. | Capponcelli S | Human mutation | 2005 | PMID: 15977174 |
Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome. | Lang GA | Cell | 2004 | PMID: 15607981 |
Mutant p53 gain of function in two mouse models of Li-Fraumeni syndrome. | Olive KP | Cell | 2004 | PMID: 15607980 |
Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. | Willis A | Oncogene | 2004 | PMID: 14743206 |
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 |
Germline TP53 mutations and Li-Fraumeni syndrome. | Varley JM | Human mutation | 2003 | PMID: 12619118 |
The IARC TP53 database: new online mutation analysis and recommendations to users. | Olivier M | Human mutation | 2002 | PMID: 12007217 |
A detailed study of loss of heterozygosity on chromosome 17 in tumours from Li-Fraumeni patients carrying a mutation to the TP53 gene. | Varley JM | Oncogene | 1997 | PMID: 9047394 |
An extended Li-Fraumeni kindred with gastric carcinoma and a codon 175 mutation in TP53. | Varley JM | Journal of medical genetics | 1995 | PMID: 8825920 |
Germ-line p53 mutations in 15 families with Li-Fraumeni syndrome. | Frebourg T | American journal of human genetics | 1995 | PMID: 7887414 |
Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. | McIntyre JF | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 1994 | PMID: 8164043 |
Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. | Birch JM | Cancer research | 1994 | PMID: 8118819 |
Crystal structure of a p53 tumor suppressor-DNA complex: understanding tumorigenic mutations. | Cho Y | Science (New York, N.Y.) | 1994 | PMID: 8023157 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/7447e408-66fd-43ee-8fc8-6012f43d7ada | - | - | - | - |
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Conditions - Somatic
Tumor type
Help
The tumor type for this variant-condition (RCV) record in ClinVar. |
Clinical impact (# of submissions)
Help
The aggregate somatic clinical impact for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate somatic clinical impact is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Oncogenicity
Help
The aggregate oncogenicity classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to the aggregate oncogenicity classification is shown in parentheses. The corresponding review status for the RCV record is indicated by stars. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
Variation/condition record
Help
The most recent date that a submitter evaluated this variant for the tumor type. |
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Oncogenic
criteria provided, single submitter
|
Mar 4, 2025 | RCV000421746.12 |
Submissions - Somatic
Oncogenicity
Help
The submitted oncogenicity 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) |
Tumor type
Help
The tumor type 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 somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Oncogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Neoplasm
Affected status: unknown
Allele origin:
somatic
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005094440.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
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Citations for somatic classification of this variant
HelpTitle | Author | Journal | Year | Link |
---|---|---|---|---|
Mutant p53 activates hnRNPA2B1-AGAP1-mediated exosome formation to promote esophageal squamous cell carcinoma progression. | Feng R | Cancer letters | 2023 | PMID: 37030635 |
A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. | Boettcher S | Science (New York, N.Y.) | 2019 | PMID: 31395785 |
A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1. | Loizou E | Cancer discovery | 2019 | PMID: 31068365 |
Prevalence and functional consequence of TP53 mutations in pediatric adrenocortical carcinoma: a children's oncology group study. | Wasserman JD | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 25584008 |
Mutant p53: one name, many proteins. | Freed-Pastor WA | Genes & development | 2012 | PMID: 22713868 |
Gain-of-function mutant p53 upregulates CXC chemokines and enhances cell migration. | Yeudall WA | Carcinogenesis | 2012 | PMID: 22114072 |
Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. | Xu J | Nature chemical biology | 2011 | PMID: 21445056 |
A common gain of function of p53 cancer mutants in inducing genetic instability. | Liu DP | Oncogene | 2010 | PMID: 19881536 |
Lack of correlation between p53-dependent transcriptional activity and the ability to induce apoptosis among 179 mutant p53s. | Kakudo Y | Cancer research | 2005 | PMID: 15781620 |
Mutant p53 exerts a dominant negative effect by preventing wild-type p53 from binding to the promoter of its target genes. | Willis A | Oncogene | 2004 | PMID: 14743206 |
Quantitative analysis of residual folding and DNA binding in mutant p53 core domain: definition of mutant states for rescue in cancer therapy. | Bullock AN | Oncogene | 2000 | PMID: 10713666 |
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Text-mined citations for rs28934578 ...
HelpRecord last updated Jun 29, 2025
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.