ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.542G>A (p.Arg181His)
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.
Pathogenic(3); Likely pathogenic(14); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000546.6(TP53):c.542G>A (p.Arg181His)
Variation ID: 142320 Accession: VCV000142320.63
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17p13.1 17: 7675070 (GRCh38) [ NCBI UCSC ] 17: 7578388 (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 Oct 9, 2016 May 1, 2024 Jan 25, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000546.6:c.542G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg181His missense NM_001126112.3:c.542G>A NP_001119584.1:p.Arg181His missense NM_001126113.3:c.542G>A NP_001119585.1:p.Arg181His missense NM_001126114.3:c.542G>A NP_001119586.1:p.Arg181His missense NM_001126115.2:c.146G>A NP_001119587.1:p.Arg49His missense NM_001126116.2:c.146G>A NP_001119588.1:p.Arg49His missense NM_001126117.2:c.146G>A NP_001119589.1:p.Arg49His missense NM_001126118.2:c.425G>A NP_001119590.1:p.Arg142His missense NM_001276695.3:c.425G>A NP_001263624.1:p.Arg142His missense NM_001276696.3:c.425G>A NP_001263625.1:p.Arg142His missense NM_001276697.3:c.65G>A NP_001263626.1:p.Arg22His missense NM_001276698.3:c.65G>A NP_001263627.1:p.Arg22His missense NM_001276699.3:c.65G>A NP_001263628.1:p.Arg22His missense NM_001276760.3:c.425G>A NP_001263689.1:p.Arg142His missense NM_001276761.3:c.425G>A NP_001263690.1:p.Arg142His missense NC_000017.11:g.7675070C>T NC_000017.10:g.7578388C>T NG_017013.2:g.17481G>A LRG_321:g.17481G>A LRG_321t1:c.542G>A LRG_321p1:p.Arg181His P04637:p.Arg181His - Protein change
- R142H, R181H, R49H, R22H
- Other names
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- Canonical SPDI
- NC_000017.11:7675069: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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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00001
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Exome Aggregation Consortium (ExAC) 0.00002
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
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 |
3307 | 3402 |
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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Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
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Jul 28, 2023 | RCV000131382.24 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Jan 25, 2024 | RCV000168247.23 | |
Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Aug 15, 2023 | RCV000255239.17 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV000576528.8 | |
Likely pathogenic (1) |
no assertion criteria provided
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Mar 4, 2021 | RCV001391195.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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May 28, 2019 | RCV000989718.4 | |
Pathogenic (1) |
no assertion criteria provided
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Mar 19, 2021 | RCV001527471.4 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Sep 10, 2023 | RCV003462011.1 |
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
(Feb 13, 2020)
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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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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000731671.3
First in ClinVar: Apr 09, 2018 Last updated: Jul 04, 2020 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Likely pathogenic
(Mar 20, 2015)
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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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Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449803.1
First in ClinVar: Dec 10, 2020 Last updated: Dec 10, 2020 |
Number of individuals with the variant: 10
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Pathogenic
(Dec 05, 2019)
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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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Genetic Services Laboratory, University of Chicago
Accession: SCV002067416.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.542G>A, in exon 5 that results in an amino acid change, p.Arg181His. This sequence … (more)
DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.542G>A, in exon 5 that results in an amino acid change, p.Arg181His. This sequence change has been described in the gnomAD database with a low population frequency of 0.0014% (dbSNP rs397514495). The p.Arg181His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg181His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This pathogenic sequence change has been previously reported in multiple individuals with TP53-related cancers such as breast cancer, adrenocortical carcinoma, and pancreatic cancer (PMIDs: 1591732, 1631137, 21059199, 30653764). Functional studies have demonstrated that the p.Arg181His change may impact protein function (PMIDs: 15580553, 21343334, 20128691). Furthermore, other nucleotide changes affecting the Arg181 residue have also been reported in individuals with TP53-related cancers suggesting that this residue is functionally and clinically important (PMIDs:1581912, 8308926, 15925506). (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: SCV002582381.1
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: SCV002583041.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
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Uncertain significance
(May 14, 2021)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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Cancer Variant Interpretation Group UK, Institute of Cancer Research, London
Accession: SCV002760195.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
Data included in classification: UK family: Mother breast cancer at 46, daughter breast cancer at 37, family history of breast cancer, brain tumour and haemangiosarcoma … (more)
Data included in classification: UK family: Mother breast cancer at 46, daughter breast cancer at 37, family history of breast cancer, brain tumour and haemangiosarcoma Brand et al 2018: 1 patient Baek et al 2019: 1 patient adrenocortical carcinoma Borresen et al 1992: 1 patient breast cancer at 31yrs Heymann et al 2010: 1 patient breast cancer 29yrs Raymond et al 2013: 1 patient adrenocortical carcinoma GeneDx case (contacted due to ClinVar entry): 1 patient meeting Chompret Ambry genetics (ClinVar entry): 3 patients meet Chompret Color Genetics (ClinVar entry): 1 patient meets Chompret 5.5 points (11 x patients meeting Chompret criteria) (PS4_str) aGVGD score = C25, bayes del 0.258 (PP3_sup) Data not included in classification: Kato et al, 2003- partially functional (>20 but <75%) Giacomelli et al, 2018 - unclassified (has DNE score but not LOF) Fortuno et al - Bayesdel 0.258 suggested prediction = pathogenic 9 germline cases on IARC 4 heterozygotes in gnomAD non-cancer (v2.1.1) – 3 male, 1 female (less)
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Likely pathogenic
(Mar 16, 2017)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000677774.2
First in ClinVar: Jan 07, 2018 Last updated: Dec 24, 2022 |
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Likely pathogenic
(Apr 16, 2023)
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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: SCV000322072.10
First in ClinVar: Oct 09, 2016 Last updated: Apr 23, 2023 |
Comment:
Observed in individuals with early-onset breast and other Li-Fraumeni-related cancers, but does not appear to result in classic Li-Fraumeni syndrome (Borreson et al., 1992; Heymann … (more)
Observed in individuals with early-onset breast and other Li-Fraumeni-related cancers, but does not appear to result in classic Li-Fraumeni syndrome (Borreson et al., 1992; Heymann et al., 2010; Raymond et al., 2013; Leongamornlert et al., 2014; Tung et al., 2015; O'Neill et al., 2017; Shindo et al., 2017; Brand et al., 2018; Mersch et al., 2018; Qian et al., 2018; Baek et al., 2019; Maxwell et al., 2021; Gillani et al., 2022); Published functional studies demonstrate defective binding and transactivation of apoptotic target genes with a consequent impact on apoptotic activity, and mixed results regarding transactivation of other p53 response elements and growth suppression (Wang et al., 1996; Flaman et al., 1998; Campomenosi et al., 2001; Kato et al., 2003; Monti et al., 2007; Malcikova et al., 2010; Schlereth et al., 2010; Monti et al., 2011; Hekmat-Scafe et al., 2016; Kotler et al., 2018; Giacomelli et al., 2018; Ben-Cohen et al., 2022; Klimovich et al., 2022); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21059199, 11793474, 24729566, 27586204, 17311302, 7981076, 8308926, 31543368, 30840781, 35043155, 36353970, 1591732, 20128691, 9546439, 17606709, 21343334, 20471942, 27101868, 26650777, 26484312, 25625332, 15580553, 24449472, 14559903, 1631137, 26762747, 27873457, 11429705, 25186627, 29979965, 28724667, 28767289, 29522266, 23175693, 28861920, 15221755, 18818522, 28772290, 26000489, 30067863, 30653764, 30264118, 24556621, 29300620, 29077256, 31056747, 31115261, 8675009, 1581912, 31026031, 30720243, 31119730, 15925506, 30352134, 30224644, 31105275, 31447099, 32676327, 32923878, 33818021, 33880204, 33194542, 33245408, 31948886, 32029870, 33230179, 35512711, 34863587, 36628428, 36262946, 35820297, 35626031, 34308104, 35875466, 15510160, 34282142, 33858029, 32817165, 34240179, 8102535, 24797764, 34725851, 28445466, 35802772, 37007070, 36831331, 36260514, 36933394, 34907344, 35659507, 34793666, 32998877) (less)
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Likely pathogenic
(Mar 11, 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: SCV001774661.2
First in ClinVar: Aug 07, 2021 Last updated: May 13, 2023 |
Comment:
Variant summary: TP53 c.542G>A (p.Arg181His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Five of … (more)
Variant summary: TP53 c.542G>A (p.Arg181His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251324 control chromosomes. c.542G>A has been reported in the literature in individuals affected with features of atypical Li-Fraumeni Syndrome and breast cancer (example, Borresen_1992, Heymann_2010, Frebourg_1992, Alyami_2021). An ascertainment of one family with this variant, identified 3 transmissions of the variant allele and 1 transmissions of the reference allele to affected individuals (Frebourg_1992). These data indicate that the variant may be associated with disease. Multiple publications report conflicting experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in severe deficiency based on the mean transactivation capacity across four different reporter strains (example, Monti_2011). However, another study reported a neutral effect on growth of malignant cells in-vitro with retained structural features of the WT protein and the somatic loss of the mutant allele in a tumor from a family reporting this variant (Frebourg_1992). Multple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Pathogenic
(Jan 23, 2023)
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criteria provided, single submitter
Method: clinical testing
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Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
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New York Genome Center
Accession: SCV004046469.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
Comment:
The c.542G>A p.(Arg181His) variant in the TP53 gene has previously been reported in multiple individuals with TP53-related cancers such as early-onset breast cancer, adrenocortical carcinoma, … (more)
The c.542G>A p.(Arg181His) variant in the TP53 gene has previously been reported in multiple individuals with TP53-related cancers such as early-onset breast cancer, adrenocortical carcinoma, leiomyosarcoma, rhabdomyosarcoma, pancreatic adenocarcinoma [PMID: 1591732, 1631137, 21059199,30653764, 28767289, 35512711, TP53 database: https://tp53.isb-cgc.org/results_germline_mutation_list] and segregates with cancer in several affected families [PMID: 1631137, 30653764, 33245408]. It has been deposited in ClinVar [ClinVar ID: 142320] as Likely Pathogenic/Pathogenic. The c.542G>A variant is observed in 6 alleles (~0.001% minor allele frequency with 0 homozygotes) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.542G>A variant in TP53 is located in exon 5 of this 11-exon gene, and predicted to replace an evolutionarily conserved arginine amino acid with histidine at position 181 in the DNA-binding domain of the encoded protein. In silico predictions are in favor of damaging effect for p.(Arg181His) [(CADD v1.6 = 25.5, REVEL = 0.797)]. Other missense alterations impacting this codon (p.Arg181Cys, p.Arg181Pro) have been reported as associated with TP53-related cancers [PMID: 27501770, 27866339, 28486781, 23484829, 15925506, 29360161]. Based on available evidence this c.542G>Ap.(Arg181His) variant identified in TP53 is classified as Pathogenic. (less)
Clinical Features:
Cardiomyopathy (present)
Secondary finding: yes
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Likely pathogenic
(Sep 08, 2023)
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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
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV004171428.1
First in ClinVar: Dec 02, 2023 Last updated: Dec 02, 2023 |
Comment:
The TP53 c.542G>A (p.Arg181His) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with … (more)
The TP53 c.542G>A (p.Arg181His) missense change has a maximum subpopulation frequency of 0.003% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). This variant has been reported in individuals with LFS-associated cancers (PMID: 1591732, 21059199, 23175693, 30067863, internal data). Computational evidence supports a deleterious effect of this variant on protein function and transactivation assays show a partially functioning allele according to Kato et al., and moderate evidence of a dominant negative effect according to Giacomelli et al. (PMID 12826609, 30224644). This variant is also a somatic hotspot in tumors. In summary, this variant meets criteria to be classified as likely pathogenic. (less)
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Likely pathogenic
(Sep 10, 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: SCV004206233.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Likely pathogenic
(Apr 11, 2022)
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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: SCV004221360.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
The frequency of this variant in the general population, 0.000031 (4/129056 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more)
The frequency of this variant in the general population, 0.000031 (4/129056 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals and families with cancer diagnoses consistent with Li-Fraumeni syndrome (PMIDs: 33818021 (2021), 28724667 (2017), 23175693 (2013), 21059199 (2010), 18689542 (2008), 1631137 (1992), 1591732 (1992)). In addition, the variant has been shown to be damaging to TP53 function in vitro (PMIDs: 21343334 (2011), 20471942 (2010), 20128691 (2010), 11896595 (2002), 11429705 (2001)). Based on the available information, this variant is classified as likely pathogenic. (less)
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Likely pathogenic
(Nov 17, 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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Color Diagnostics, LLC DBA Color Health
Accession: SCV000686749.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
Comment:
This missense variant replaces arginine with histidine at codon 181 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 181 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 reported conflicting findings on variant protein activities in yeast transactivation assays, human cell growth suppression assays, human cell proliferation assay, and TP53 tumor suppressor-associated activities (PMID: 12826609, 20471942, 29979965, 30224644, 34907344; IARC database). The IARC database reports observation of this variant in 12 individuals affected with Li-Fraumeni syndrome or Li-Fraumeni-like syndrome (http://mutantp53.broadinstitute.org/). This variant has been reported in multiple individuals affected with early-onset breast cancer and family history of multiple cancers, who meet Chompret criteria for Li-Fraumeni syndrome (PMID: 1591732, 1631137, 21059199, 33818021). A family study has shown this variant to segregate with breast cancer and leiomyosarcoma in three siblings (PMID: 1631137). This variant also has been observed in an individual affected with late-onset adrenocortical carcinoma, pheochromocytoma and glioblastoma multiforme, who had been clinically diagnosed with neurofibromatosis type 1 (PMID: 23175693). This variant has been identified in 4/282728 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different missense variants occurring at the same codon, p.Arg181Cys and p.Arg181Pro, are associated with disease (ClinVar variation ID: 125689 and 59756), indicating that arginine at this position is important for TP53 function. Based on the available evidence, this variant is classified as Likely Pathogenic. (less)
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Pathogenic
(Jan 25, 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: SCV000218918.14
First in ClinVar: Mar 29, 2015 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 181 of the TP53 protein (p.Arg181His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 181 of the TP53 protein (p.Arg181His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 1591732, 21059199, 1631137, Invitae). A review of approximately 50 individuals with this variant revealed they were less likely to meet clinical criteria for Li-Fraumeni syndrome compared to carriers of other well defined TP53 pathogenic variants (Invitae). This suggests this variant may be associated with varying or atypical clinical presentation. It is commonly reported in individuals of Arabic ancestry (PMID: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). ClinVar contains an entry for this variant (Variation ID: 142320). 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: 12826609, 20128691, 21343334, 29979965, 30224644). This variant disrupts the p.Arg181 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1581912, 17606709, 23484829, 27501770, 27866339, 28486781). 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
(Jul 28, 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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Ambry Genetics
Accession: SCV000186358.11
First in ClinVar: Aug 06, 2014 Last updated: May 01, 2024 |
Comment:
The p.R181H variant (also known as c.542G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide … (more)
The p.R181H variant (also known as c.542G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 542. The arginine at codon 181 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in a proband with early-onset breast cancer who also met Chompret criteria for TP53 testing (Borresen A et al. Cancer Res. 1992 Jun 1;52(11):3234-6), in an individual diagnosed with breast cancer at age 29 and a family history of multiple cancers (Heymann S et al. Radiat. Oncol. 2010 Nov 8;5:104), and also in an individual with adrenocortical carcinoma and clinical history of neurofibromatosis type 1 (Raymond VM et al. J. Clin. Endocrinol. Metab. 2013 Jan;98(1):E119-25). Functional studies in yeast have shown significant levels of reduced transactivation activity with the p.R181H variant (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). Other functional studies have shown that p.R181H causes a defect in promoter binding and transactivation of apoptotic target genes, causing a loss of apoptotic activity (Schlereth K et al. Mol. Cell 2010 May;38(3):356-68; Wang W et al. Genes Dev. 1996 May;10(10):1219-32), but was similar to wild type in that it does not bind proteins specific for the mutant conformation of the p53 protein (Frebourg et al. Proc Natl Acad Sci U.S.A. 1992 Jul;89(14):6413-7), and shows proficient growth suppression in human cells (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 10;50:1381-1387). This alteration demonstrated a partially reduced ability to bind DNA (Malcikova et al. Biol. Chem. 2010; 391(2-3):197-205). In addition, other missense alterations impacting this codon (p.R181C, p.R181L, and p.R181P) have been reported as associated with TP53-related disease and causing impaired function (Sidransky D et al. Cancer Res. 1992;15;52(10):2984-6; Villani A et al. Lancet Oncol. 2016 Sep;17(9):1295-305; Krutikova V et al. Eur. J. Cancer. 2005 Jul;41(11):1597-603; Kyritsis AP et al. J. Natl. Cancer Inst. 1994 Mar 2;86(5):344-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on current evidence, p.R181H is interpreted as a likely pathogenic moderate risk allele that may not be associated with classic LFS. Clinical correlation is advised. (less)
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Likely pathogenic
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Squamous cell carcinoma of the head and neck
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV001140260.1
First in ClinVar: Jan 09, 2020 Last updated: Jan 09, 2020 |
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Likely pathogenic
(Aug 15, 2023)
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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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Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV002760883.3
First in ClinVar: Dec 17, 2022 Last updated: Aug 18, 2023 |
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Likely pathogenic
(Mar 04, 2021)
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no assertion criteria provided
Method: case-control
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Carcinoma of pancreas
Affected status: yes
Allele origin:
germline
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CZECANCA consortium
Accession: SCV001593121.1
First in ClinVar: May 14, 2021 Last updated: May 14, 2021 |
Number of individuals with the variant: 1
Ethnicity/Population group: Slavic
Geographic origin: Czech Republic
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Pathogenic
(Mar 19, 2021)
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no assertion criteria provided
Method: clinical testing
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Familial cancer of breast
Affected status: no
Allele origin:
somatic
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University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738488.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
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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:
germline
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BRCAlab, Lund University
Accession: SCV002589029.1
First in ClinVar: Apr 01, 2023 Last updated: Apr 01, 2023 |
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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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Germline predisposition to pediatric Ewing sarcoma is characterized by inherited pathogenic variants in DNA damage repair genes. | Gillani R | American journal of human genetics | 2022 | PMID: 35512711 |
p53 partial loss-of-function mutations sensitize to chemotherapy. | Klimovich B | Oncogene | 2022 | PMID: 34907344 |
Clinical Features of Breast Cancer in South Korean Patients with Germline TP53 Gene Mutations. | Alyami H | Journal of breast cancer | 2021 | PMID: 33818021 |
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 |
Rare Germline Pathogenic Mutations of DNA Repair Genes Are Most Strongly Associated with Grade Group 5 Prostate Cancer. | Wu Y | European urology oncology | 2020 | PMID: 31948886 |
A quantitative model to predict pathogenicity of missense variants in the TP53 gene. | Fortuno C | Human mutation | 2019 | PMID: 30840781 |
High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering. | Soussi T | Human mutation | 2019 | PMID: 30720243 |
Li-Fraumeni syndrome presenting as cutaneous melanoma in a child: case report and review of literature. | Baek YS | Journal of the European Academy of Dermatology and Venereology : JEADV | 2019 | PMID: 30653764 |
Li-Fraumeni Syndrome. | Adam MP | - | 2019 | PMID: 20301488 |
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 |
Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. | Brand R | Cancer | 2018 | PMID: 30067863 |
A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
Effectiveness of beta-blockers depending on the genotype of congenital long-QT syndrome: A meta-analysis. | Ahn J | PloS one | 2017 | PMID: 29059199 |
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma. | Shindo K | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28767289 |
Germline Mutations in Cancer Susceptibility Genes in a Large Series of Unselected Breast Cancer Patients. | Sun J | Clinical cancer research : an official journal of the American Association for Cancer Research | 2017 | PMID: 28724667 |
Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
Recurrent TP53 missense mutation in cancer patients of Arab descent. | Zick A | Familial cancer | 2017 | PMID: 27866339 |
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 |
Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. | Villani A | The Lancet. Oncology | 2016 | PMID: 27501770 |
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 |
TP53 hotspot mutations are predictive of survival in primary central nervous system lymphoma patients treated with combination chemotherapy. | Munch-Petersen HD | Acta neuropathologica communications | 2016 | PMID: 27101868 |
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 |
Clinical Application of Multigene Panels: Challenges of Next-Generation Counseling and Cancer Risk Management. | Slavin TP | Frontiers in oncology | 2015 | PMID: 26484312 |
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 |
Integrative clinical genomics of advanced prostate cancer. | Robinson D | Cell | 2015 | PMID: 26000489 |
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 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
ERBB2 gene as a potential therapeutic target in small bowel adenocarcinoma. | Laforest A | European journal of cancer (Oxford, England : 1990) | 2014 | PMID: 24797764 |
Frequent germline deleterious mutations in DNA repair genes in familial prostate cancer cases are associated with advanced disease. | Leongamornlert D | British journal of cancer | 2014 | PMID: 24556621 |
Increased oxidative metabolism in the Li-Fraumeni syndrome. | Wang PY | The New England journal of medicine | 2013 | PMID: 23484829 |
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 |
Prevalence of germline TP53 mutations in a prospective series of unselected patients with adrenocortical carcinoma. | Raymond VM | The Journal of clinical endocrinology and metabolism | 2013 | PMID: 23175693 |
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 |
TP53 mutation is frequently associated with CTNNB1 mutation or MYCN amplification and is compatible with long-term survival in medulloblastoma. | Pfaff E | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2010 | PMID: 21060032 |
Radio-induced malignancies after breast cancer postoperative radiotherapy in patients with Li-Fraumeni syndrome. | Heymann S | Radiation oncology (London, England) | 2010 | PMID: 21059199 |
DNA binding cooperativity of p53 modulates the decision between cell-cycle arrest and apoptosis. | Schlereth K | Molecular cell | 2010 | PMID: 20471942 |
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 |
Mutant p53 protein localized in the cytoplasm inhibits autophagy. | Morselli E | Cell cycle (Georgetown, Tex.) | 2008 | PMID: 18818522 |
Monoallelic TP53 inactivation is associated with poor prognosis in chronic lymphocytic leukemia: results from a detailed genetic characterization with long-term follow-up. | Zenz T | Blood | 2008 | PMID: 18689542 |
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 |
Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: lessons from recent developments in the IARC TP53 database. | Petitjean A | Human mutation | 2007 | PMID: 17311302 |
Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations. | Krutilkova V | European journal of cancer (Oxford, England : 1990) | 2005 | PMID: 15925506 |
Reassessment of the TP53 mutation database in human disease by data mining with a library of TP53 missense mutations. | Soussi T | Human mutation | 2005 | PMID: 15580553 |
Functional protein microarrays for parallel characterisation of p53 mutants. | Boutell JM | Proteomics | 2004 | PMID: 15221755 |
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 |
Tumour p53 mutations exhibit promoter selective dominance over wild type p53. | Monti P | Oncogene | 2002 | PMID: 11896595 |
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 mutants can often transactivate promoters containing a p21 but not Bax or PIG3 responsive elements. | Campomenosi P | Oncogene | 2001 | PMID: 11429705 |
Identification of human p53 mutations with differential effects on the bax and p21 promoters using functional assays in yeast. | Flaman JM | Oncogene | 1998 | PMID: 9546439 |
The XPB and XPD DNA helicases are components of the p53-mediated apoptosis pathway. | Wang XW | Genes & development | 1996 | PMID: 8675009 |
Germline p53 gene mutations in subsets of glioma patients. | Kyritsis AP | Journal of the National Cancer Institute | 1994 | PMID: 8308926 |
Alteration of p53 gene in ovarian carcinoma: clinicopathological correlation and prognostic significance. | Niwa K | British journal of cancer | 1994 | PMID: 7981076 |
Prognostic significance of TP53 alterations in breast carcinoma. | Andersen TI | British journal of cancer | 1993 | PMID: 8102535 |
Germ-line mutations of the p53 tumor suppressor gene in patients with high risk for cancer inactivate the p53 protein. | Frebourg T | Proceedings of the National Academy of Sciences of the United States of America | 1992 | PMID: 1631137 |
Screening for germ line TP53 mutations in breast cancer patients. | Børresen AL | Cancer research | 1992 | PMID: 1591732 |
Inherited p53 gene mutations in breast cancer. | Sidransky D | Cancer research | 1992 | PMID: 1581912 |
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Text-mined citations for rs397514495 ...
HelpRecord last updated May 01, 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.