The NM_000546.6: c.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, SCV000186052.8). This variant has an allele frequency of 0.00001186 (14/1179946 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed 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: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 ). Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) 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). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PS2, PM2_Supporting, PS3, PP4_Moderate, PM1, PP3. (Bayesian Points: 22; VCEP specifications version 2.0; 7/24/2024).
ClinVar Genomic variation as it relates to human health
NM_000546.6(TP53):c.818G>A (p.Arg273His)
Germline
Reviewed by expert panel
Help
Reviewed by expert panel. Learn more about how ClinVar calculates review status.
Pathogenic
for
Li-Fraumeni syndrome
Classification is based on the expert panel submission
Aug 2024 by
ClinGen TP53 Variant Curation Expert Panel, ClinGen
Help
FDA Recognized Database
The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Somatic
No data submitted for somatic clinical impact
Somatic
Oncogenicity
Help
criteria provided, single submitter. Learn more about how ClinVar calculates review status.
Oncogenic
This classification is based on the single submission received
Help
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.
1
Variant Details
- Identifiers
-
NM_000546.6(TP53):c.818G>A (p.Arg273His)
Variation ID: 12366 Accession: VCV000012366.74
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 17p13.1 17: 7673802 (GRCh38) [ NCBI UCSC ] 17: 7577120 (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 Apr 8, 2013 Jun 29, 2025 Aug 5, 2024 Somatic - Oncogenicity Aug 11, 2024 Mar 11, 2025 Mar 4, 2025 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000546.6:c.818G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000537.3:p.Arg273His missense NM_000546.5(TP53):c.818G>A NM_001126112.3:c.818G>A NP_001119584.1:p.Arg273His missense NM_001126113.3:c.818G>A NP_001119585.1:p.Arg273His missense NM_001126114.3:c.818G>A NP_001119586.1:p.Arg273His missense NM_001126115.2:c.422G>A NP_001119587.1:p.Arg141His missense NM_001126116.2:c.422G>A NP_001119588.1:p.Arg141His missense NM_001126117.2:c.422G>A NP_001119589.1:p.Arg141His missense NM_001126118.2:c.701G>A NP_001119590.1:p.Arg234His missense NM_001276695.3:c.701G>A NP_001263624.1:p.Arg234His missense NM_001276696.3:c.701G>A NP_001263625.1:p.Arg234His missense NM_001276697.3:c.341G>A NP_001263626.1:p.Arg114His missense NM_001276698.3:c.341G>A NP_001263627.1:p.Arg114His missense NM_001276699.3:c.341G>A NP_001263628.1:p.Arg114His missense NM_001276760.3:c.701G>A NP_001263689.1:p.Arg234His missense NM_001276761.3:c.701G>A NP_001263690.1:p.Arg234His missense NC_000017.11:g.7673802C>T NC_000017.10:g.7577120C>T NG_017013.2:g.18749G>A LRG_321:g.18749G>A LRG_321t1:c.818G>A LRG_321p1:p.Arg273His LRG_321t5:c.422G>A LRG_321p5:p.Arg141His P04637:p.Arg273His - Protein change
- R273H, R141H, R234H, R114H
- Other names
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p.R273H:CGT>CAT
- Canonical SPDI
- NC_000017.11:7673801: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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0.00020 (T)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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Trans-Omics for Precision Medicine (TOPMed) 0.00002
1000 Genomes Project 0.00020
1000 Genomes Project 30x 0.00031
- 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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
May 22, 2024 | RCV000013163.44 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jan 1, 1993 | RCV000013164.13 | |
| Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
|
Mar 4, 2025 | RCV000254693.33 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Jun 6, 2022 | RCV000431361.12 | |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV000422097.12 | |
| Pathogenic (7) |
reviewed by expert panel
|
Aug 5, 2024 | RCV000463420.27 | |
| Pathogenic/Likely pathogenic (2) |
no assertion criteria provided
|
Mar 19, 2021 | RCV000785345.11 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001358389.10 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2021 | RCV001527484.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Mar 19, 2021 | RCV001527470.10 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 29, 2024 | RCV000115738.24 | |
| Pathogenic (1) |
no assertion criteria provided
|
Sep 1, 2020 | RCV001257517.9 | |
| Pathogenic (1) |
no assertion criteria provided
|
Jul 1, 2021 | RCV003162246.8 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Mar 30, 2024 | RCV003466853.2 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Jan 26, 2023 | RCV003492292.1 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 18, 2024 | RCV005003353.1 | |
|
TP53-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
Oct 1, 2024 | RCV004797590.1 |
| 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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|---|---|---|---|---|---|
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Pathogenic
(Aug 05, 2024)
C
Contributing to aggregate classification
|
reviewed by expert panel
Method: curation
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen TP53 Variant Curation Expert Panel, ClinGen
FDA Recognized Database
Accession: SCV001142550.2 First in ClinVar: Jan 12, 2020 Last updated: Aug 18, 2024 |
Comment:
The NM_000546.6: c.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant … (more)
The NM_000546.6: c.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, SCV000186052.8). This variant has an allele frequency of 0.00001186 (14/1179946 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed 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: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 ). Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) 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). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PS2, PM2_Supporting, PS3, PP4_Moderate, PM1, PP3. (Bayesian Points: 22; VCEP specifications version 2.0; 7/24/2024). (less)
|
|
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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: SCV001478190.1
First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021 |
|
|
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Pathogenic
(Mar 18, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605425.2
First in ClinVar: Sep 30, 2017 Last updated: Jan 08, 2022 |
Comment:
The TP53 c.818G>A, p.Arg273His variant (rs28934576), has been reported in multiple patients diagnosed with Li-Fraumeni syndrome (Curry 2011, Khayat 2004, Malkin 1992, Park 2016, Schlegelberger … (more)
The TP53 c.818G>A, p.Arg273His variant (rs28934576), has been reported in multiple patients diagnosed with Li-Fraumeni syndrome (Curry 2011, Khayat 2004, Malkin 1992, Park 2016, Schlegelberger 2015, Siddiqui 2005, Tsaousis 2019, Zerdoumi 2012). Functional characterization of the variant protein indicates a defect in the transactivation of TP53 targets (Malcikova 2010, Monti 2007, Monti 2011, Zerdoumi 2012) and repression of genes involved in cell proliferation (Scian 2004). This results in an increase in growth, invasiveness, and resistance to apoptosis of cell lines upon DNA damage (Kalo 2012, Li 2014). This variant is found in the general population with an allele frequency of 0.0016% (4/251054 alleles) in the Genome Aggregation Database. The arginine at residue 273 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.868). Based on the above information, the variant is classified as pathogenic. References: Curry S et al. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation. Pediatr Dev Pathol. 2011; 14(3):248-51. Kalo E et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci. 2012; 125(Pt 22):5578-86. Khayat C et al. Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatr Blood Cancer. 2004; 43(6):683-6. Li J et al. Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy. Hum Mutat. 2014; 35(5):575-84. Malcikova J et al. Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. Biol Chem. 2010; 391(2-3):197-205. Malkin D et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992; 326(20):1309-15. Monti P et al. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Cancer Res. 2007; 13(13):3789-95. Monti P et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011; 9(3):271-9. Schlegelberger B et al. A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. Pediatr Blood Cancer. 2015; 62(8):1481-4. Scian M et al. Modulation of gene expression by tumor-derived p53 mutants. Cancer Res. 2004; 64(20):7447-54. Siddiqui R et al. The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. Fam Cancer. 2005; 4(2):177-81. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Zerdoumi Y et al. Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. Hum Mutat. 2013; 34(3):453-61. (less)
|
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Pathogenic
(Nov 23, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV002059231.1
First in ClinVar: Jan 15, 2022 Last updated: Jan 15, 2022 |
|
|
|
Pathogenic
(Apr 03, 2019)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002072052.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.818G>A, in exon 8 that results in an amino acid change, p.Arg273His. This sequence … (more)
DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.818G>A, in exon 8 that results in an amino acid change, p.Arg273His. This sequence change has been described in the gnomAD database with a low global population frequency of 0.01% (dbSNP rs28934576). This pathogenic sequence change has previously been described in multiple patients and families with Li Fraumeni syndrome (PMIDs: 1565144, 21054160, 25584008). The p.Arg273His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg273 amino acid residue has multiple other amino acid substitutions that are reported to be pathogenic, including p.Arg273Leu, p.Arg273Gly, p.Arg273Ser, and p.Arg273Cys (PMIDs: 10864200, 8425176, 8164043, 8479749). Functional assays demonstrate that the p.Arg273His change results in deficient transactivation activity and results in a dominant negative effect over wild-type p53 (PMIDs: 12826609, 17636407). The p.Arg273His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). (less)
|
|
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Pathogenic
(Jun 06, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: research
|
Lung adenocarcinoma
Affected status: yes
Allele origin:
somatic
|
Liquid Biopsy and Cancer Interception Group, Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research
Accession: SCV003806294.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Number of individuals with the variant: 1
|
|
|
Likely pathogenic
(Jan 26, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Breast and/or ovarian cancer
Affected status: unknown
Allele origin:
germline
|
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Accession: SCV004239792.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Apr 28, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
All of Us Research Program, National Institutes of Health
Accession: SCV004823764.1
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:
The c.818G>A (p.Arg273His) variant of the TP53 gene replaces arginine with histidine at codon 273 of the TP53 protein. This variant has been reported in … (more)
The c.818G>A (p.Arg273His) variant of the TP53 gene replaces arginine with histidine at codon 273 of the TP53 protein. This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, it has been observed as a de novo variant in a proband with breast cancer at age 29 (PMID: 12672316). This variant is within a codon that is an established mutational hotspot in the TP53 gene (PMID: 2046748). Functional studies have shown that the variant results in non-functional of the protein (PMID: 12826609) and evidence of a dominant negative effect and loss of function (PMID: 30224644). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (a BayesDel score > 0.16 and Align-GVGD is C25). Based on the supporting evidence, the c.818G>A (p.Arg273His) variant in TP53 is interpreted as pathogenic. (less)
Number of individuals with the variant: 2
Zygosity: Single Heterozygote
|
|
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Pathogenic
(Nov 03, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848862.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg273His variant in TP53 has been reported in at least 6 individuals with Li-Fraumeni syndrome and as a de novo occurence in an individual … (more)
The p.Arg273His variant in TP53 has been reported in at least 6 individuals with Li-Fraumeni syndrome and as a de novo occurence in an individual with breast cancer (selected publications Wong 2006 PMID: 16401470, Khayat 2004 PMID: 15390294, Varley 1997 PMID: 9242456, Chompret 2000 PMID: 10864200, Malkin 1992 PMID: 1565144, Flaman 1995 PMID: 7732013, Lalloo 2003 PMID: 12672316) and it was classified as pathogenic on August 28, 2019 by the ClinGen-approved ClinGen TP53 Variant Curation Expert Panel (Variation ID 12366). It has also been identified in 2/68014 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is within a codon that is an established hotspot in the TP53 gene (Levine 1991 PMID: 2046748). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro transactivation assays show a low functioning allele and there is evidence of a dominant negative effect and loss of function (Kato 2003 PMID: 12826609, Giacomelli 2018 PMID: 30224644). In summary, the p.Arg273His meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PS2, PM2_Supporting. (less)
|
|
|
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: SCV005685072.1
First in ClinVar: Feb 01, 2025 Last updated: Feb 01, 2025 |
Comment:
The following ACMG criteria was used: PS4_VS, PS2, PM2_SUP, PS3, PP4_MOD, PM1, PP3
|
|
|
Pathogenic
(Feb 02, 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: SCV000545317.11
First in ClinVar: Apr 17, 2017 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 273 of the TP53 protein (p.Arg273His). … (more)
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 273 of the TP53 protein (p.Arg273His). 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 missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (LFS) (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12366). 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: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
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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: SCV001450494.2
First in ClinVar: Dec 12, 2020 Last updated: Apr 13, 2025 |
Age: 50-59 years
Sex: male
Geographic origin: Sri Lanka
|
|
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Pathogenic
(Apr 16, 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: SCV001735236.3
First in ClinVar: Jun 19, 2021 Last updated: May 03, 2025 |
Comment:
This missense variant replaces arginine with histidine at codon 273 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 273 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 the mutant protein to be non-functional in transactivation assays (IARC database, PMID: 12826609, 20407015, 25584008) and cell growth assays (PMID: 24677579, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 1565144, 7732013, 10864200, 15390294, 16401470, 27374712) and in individuals meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 9242456, 25584008, 25787918). This variant has been identified in 4/251054 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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Likely pathogenic
(Jan 01, 2020)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
|
GeneKor MSA
Accession: SCV000821786.2
First in ClinVar: Oct 10, 2018 Last updated: May 04, 2020 |
Comment:
This sequence change replaces Arginine with Histidine at codon 273 of the TP53 protein. The arginine residue is highly conserved among species and is located … (more)
This sequence change replaces Arginine with Histidine at codon 273 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and histidine (Grantham Score 29). There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934576, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 17540308, 1565144, 20693561). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels(PMID: 12826609). In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID: 12366) (less)
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Pathogenic
(Apr 26, 2017)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV000602280.2
First in ClinVar: Sep 28, 2017 Last updated: Jan 01, 2022 |
|
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Pathogenic
(Jul 02, 2018)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV000839110.2
First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022 |
|
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Pathogenic
(Sep 10, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
germline
|
New York Genome Center
Accession: SCV002764339.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
The c.818G>A, p.Arg273His missense variant in TP53 has been reported in several individuals meeting classic Li-Fraumeni or Chompret criteria,occurring de novo in at least one … (more)
The c.818G>A, p.Arg273His missense variant in TP53 has been reported in several individuals meeting classic Li-Fraumeni or Chompret criteria,occurring de novo in at least one individual and segregating with disease in affected families (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135). This variant is located in the DNA-binding domain of the TP53 protein and is defined as a contact mutation that eliminates an essential DNA contact (PMID: 20516128). A mutant mouse model for this variant develops various tumors and carcinomas by recapitulating LFS (PMID: 15607980). In addition, experimental studies have shown that this variant disrupts transcriptional activity in yeast-based assays (PMID: 12826609) and enhances cell proliferation, invasion, migration, and drug resistance in vitro (PMID:17636407, 24677579). This variant has three heterozygous alleles in the gnomAD v3.1.1 database, suggesting it is not a common benign variant in the populations represented in this database. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, this variant is classified as pathogenic. (less)
Clinical Features:
Hepatic steatosis (present) , Type 2 diabetes mellitus (present) , Hyperlipidemia (present)
Test name: whole genome sequencing
Zygosity: Single Heterozygote
Secondary finding: yes
Platform name: NovaSeq 6000
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Pathogenic
(Apr 29, 2022)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000149647.15
First in ClinVar: May 17, 2014 Last updated: Mar 04, 2023 |
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity … (more)
Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Monti 2011, Wasserman 2015, Kotler 2018); This variant is associated with the following publications: (PMID: 23334668, 20128691, 7732013, 10864200, 18511570, 25896519, 23484829, 29324801, 32039725, 15492269, 17606709, 22811390, 23559009, 22899716, 24573247, 24677579, 25958320, 26703669, 17636407, 25433984, 26332594, 8423216, 20693561, 21054160, 1565144, 21552135, 21484931, 25584008, 23172776, 17540308, 27798748, 25530302, 27498048, 27323394, 27287813, 27346245, 27659839, 27374712, 28091804, 27501770, 25787918, 1447251, 9242456, 12672316, 16401470, 28509937, 20522432, 27831900, 26225655, 26681312, 28453743, 21761402, 16096528, 29489754, 28472496, 21343334, 26585234, 28861920, 29752822, 15607980, 30287823, 30720243, 30092803, 30840781, 31159747, 15951970, 22851211, 28369373, 31105275, 32475984, 32156018, 33300245, 34308366, 32817165, 33372952, 31958074, 33332384, 33245408, 32427313, 33087929, 33144694, 29979965, 15510160) (less)
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Pathogenic
(May 11, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004043518.2
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: 9399838]. Functional studies indicate this … (more)
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9399838]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 14743206, 19454241, 24677579]. This variant is expected to disrupt protein structure [PMID: 24677579, Myriad internal data]. (less)
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Pathogenic
(Mar 30, 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: SCV004206253.2
First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024 |
|
|
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Pathogenic
(Apr 18, 2024)
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: SCV000697450.2
First in ClinVar: Dec 26, 2017 Last updated: Jul 15, 2024 |
Comment:
Variant summary: TP53 c.818G>A (p.Arg273His) results in a non-conservative amino acid change located in the p53, DNA-binding domain of the encoded protein sequence. Four of … (more)
Variant summary: TP53 c.818G>A (p.Arg273His) results in a non-conservative amino acid change located in the p53, DNA-binding domain 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 1.6e-05 in 251054 control chromosomes. c.818G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Bougeard_2015, Varley_1997, Wasserman_2015). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.817C>T, p.Arg273Cys), supporting the critical relevance of codon 273 to TP53 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishing TP53 binding (Wasserman_2015) and functional inactiviation (Lang_2004). The following publications have been ascertained in the context of this evaluation (PMID: 25584008, 26014290, 9242456, 15607981). ClinVar contains an entry for this variant (Variation ID: 12366). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 22, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV005402346.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Comment:
The TP53 c.818G>A (p.Arg273His) missense change a maximum founder subpopulation frequency of 0.01% and a maximum non-founder subpopulation frequency of 0.003% in gnomAD v2.1.1 (http://gnomad.broadinstitute.org). … (more)
The TP53 c.818G>A (p.Arg273His) missense change a maximum founder subpopulation frequency of 0.01% and a maximum non-founder 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: 10645809, 10864200, 16401470, 22851211, 25787918, internal data). Computational evidence supports a deleterious effect of this variant on protein function. Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID: 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic. (less)
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Pathogenic
(Aug 29, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000186052.10
First in ClinVar: Aug 06, 2014 Last updated: Jan 13, 2025 |
Comment:
The p.R273H pathogenic mutation (also known as c.818G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at … (more)
The p.R273H pathogenic mutation (also known as c.818G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 818. The arginine at codon 273 is replaced by histidine, an amino acid with highly similar properties. This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including soft tissue and osteosarcomas, breast cancer, and central nervous system malignancies (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum. Mutat. 2007 Jun;28(6):622-9). In addition, 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). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and 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 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. (less)
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Pathogenic
(Apr 18, 2024)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
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
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: unknown
Allele origin:
germline
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000611327.3
First in ClinVar: Nov 11, 2017 Last updated: Jan 25, 2025 |
|
|
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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: SCV004026686.2
First in ClinVar: Aug 19, 2023 Last updated: Mar 11, 2025 |
|
|
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Pathogenic
(Jun 17, 2021)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001762058.2
First in ClinVar: Jul 31, 2021 Last updated: Apr 13, 2025 |
Clinical Features:
Breast carcinoma (present)
Sex: female
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Pathogenic
(Jul 20, 2023)
N
Not contributing to aggregate classification
|
criteria provided, single submitter
Method: clinical testing
|
Li-Fraumeni syndrome 1
Affected status: yes
Allele origin:
germline
|
3billion
Accession: SCV002572762.3
First in ClinVar: Sep 17, 2022 Last updated: Jun 29, 2025 |
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in … (more)
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012366 /PMID: 1565144) and different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser / ClinVar ID: VCV000043594, VCV000231060, VCV000376655, VCV000376656, VCV000634682 /PMID: 10864200, 11180592, 8164043, 8425176, 8479749) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 12672316). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10864200, 15390294, 1565144, 16401470, 7732013, 9242456). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Platform type: exome sequencing
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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: SCV000190004.1
First in ClinVar: Oct 19, 2014 Last updated: Oct 19, 2014 |
|
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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: SCV000692068.1
First in ClinVar: Feb 19, 2018 Last updated: Feb 19, 2018 |
|
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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: SCV000923913.1
First in ClinVar: Jun 17, 2019 Last updated: Jun 17, 2019 |
Observation 1:
Platform type: next-gen sequencing
Observation 2:
Platform type: next-gen sequencing
|
|
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Pathogenic
(Sep 01, 2020)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: provider interpretation
|
Rhabdomyosarcoma
Affected status: yes
Allele origin:
germline
|
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Accession: SCV001434343.1
First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020 |
|
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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: SCV002758479.1
First in ClinVar: Apr 15, 2023 Last updated: Apr 15, 2023 |
|
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Pathogenic
(Jan 01, 1993)
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: SCV000033410.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2013 |
Comment on evidence:
Malkin et al. (1992) identified a germline CGT-to-CAT mutation in exon 8 of the p53 gene that converted arg273 to his (R273H). The proband was … (more)
Malkin et al. (1992) identified a germline CGT-to-CAT mutation in exon 8 of the p53 gene that converted arg273 to his (R273H). The proband was a male in whom soft-tissue sarcoma was discovered at the age of 22 years and gastric carcinoma at the age of 30 years (see LFS; 151623). In 5 of 6 anaplastic carcinomas of the thyroid and in an anaplastic carcinoma thyroid cell line ARO, Fagin et al. (1993) identified the R273H mutation. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggested that inactivation of p53 may confer these neoplasms with aggressive properties and may further loss of differentiated function. (less)
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Pathogenic
(Jan 01, 1993)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: literature only
|
THYROID CARCINOMA, ANAPLASTIC, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000033411.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 08, 2013 |
Comment on evidence:
Malkin et al. (1992) identified a germline CGT-to-CAT mutation in exon 8 of the p53 gene that converted arg273 to his (R273H). The proband was … (more)
Malkin et al. (1992) identified a germline CGT-to-CAT mutation in exon 8 of the p53 gene that converted arg273 to his (R273H). The proband was a male in whom soft-tissue sarcoma was discovered at the age of 22 years and gastric carcinoma at the age of 30 years (see LFS; 151623). In 5 of 6 anaplastic carcinomas of the thyroid and in an anaplastic carcinoma thyroid cell line ARO, Fagin et al. (1993) identified the R273H mutation. The presence of p53 mutations almost exclusively in poorly differentiated thyroid tumors and thyroid cancer cell lines suggested that inactivation of p53 may confer these neoplasms with aggressive properties and may further loss of differentiated function. (less)
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Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Malignant tumor of breast
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: SCV001554107.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The TP53 p.Arg273His variant was identified in 2 of 942 proband chromosomes (frequency: 0.002) from individuals or families with Li Fraumeni Syndrome or thyroid cancer … (more)
The TP53 p.Arg273His variant was identified in 2 of 942 proband chromosomes (frequency: 0.002) from individuals or families with Li Fraumeni Syndrome or thyroid cancer (Masciari 2011, Romei 2017) and reported in multiple case studies in individuals or families with Li-Fraumeni Syndrome (Bemis 2007, Sugawara 2011, Baumuller 2010). In addition, the variant was reported as a somatic mutation in breast cancer, colorectal cancer, non-small cell lung cancer or high-grade glioma tissues (Jiang 2018, Heath-2018, Li 2018). The variant was also identified in dbSNP (ID: rs28934576) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and eight other submitters; as likely pathogenic by two submitters), and in LOVD 3.0 (2x as pathogenic). The variant was identified in control databases in 4 of 245868 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111470 chromosomes (freq: 0.00003), Ashkenazi Jewish in 1 of 9842 chromosomes (freq: 0.0001), but not in the African, Other, Latino, East Asian, Finnish, or South Asian populations. Several functional studies suggests the variant enhances cell migration, invasion abilities, influences apoptosis, leads to more aggressive phenotypes, and enhances cancer cell malignancy (Kang 2018, Joerger 2010, Dong 2007, Li 2014). The p.Arg273 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. (less)
Number of individuals with the variant: 1
|
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Pathogenic
(Mar 19, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Multiple myeloma
Colorectal cancer
Affected status: yes
Allele origin:
somatic
|
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738487.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021
Comment:
Related to multiple myeloma
|
Secondary finding: yes
|
|
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Pathogenic
(Mar 19, 2021)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
Ovarian cancer
Affected status: no
Allele origin:
somatic
|
University Health Network, Princess Margaret Cancer Centre
Accession: SCV001738490.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
|
|
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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: SCV001738505.1
First in ClinVar: Jun 26, 2021 Last updated: Jun 26, 2021 |
Secondary finding: yes
|
|
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Pathogenic
(Oct 01, 2024)
N
Not contributing to aggregate classification
|
no assertion criteria provided
Method: clinical testing
|
TP53-related disorder
Affected status: yes
Allele origin:
germline
|
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV005419164.1
First in ClinVar: Dec 07, 2024 Last updated: Dec 07, 2024 |
|
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Likely pathogenic
(Feb 22, 2017)
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: SCV000677727.3
First in ClinVar: Oct 19, 2014 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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Comment:
Comment:
The TP53 c.818G>A, p.Arg273His variant (rs28934576), has been reported in multiple patients diagnosed with Li-Fraumeni syndrome (Curry 2011, Khayat 2004, Malkin 1992, Park 2016, Schlegelberger 2015, Siddiqui 2005, Tsaousis 2019, Zerdoumi 2012). Functional characterization of the variant protein indicates a defect in the transactivation of TP53 targets (Malcikova 2010, Monti 2007, Monti 2011, Zerdoumi 2012) and repression of genes involved in cell proliferation (Scian 2004). This results in an increase in growth, invasiveness, and resistance to apoptosis of cell lines upon DNA damage (Kalo 2012, Li 2014). This variant is found in the general population with an allele frequency of 0.0016% (4/251054 alleles) in the Genome Aggregation Database. The arginine at residue 273 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.868). Based on the above information, the variant is classified as pathogenic. References: Curry S et al. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation. Pediatr Dev Pathol. 2011; 14(3):248-51. Kalo E et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci. 2012; 125(Pt 22):5578-86. Khayat C et al. Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatr Blood Cancer. 2004; 43(6):683-6. Li J et al. Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy. Hum Mutat. 2014; 35(5):575-84. Malcikova J et al. Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. Biol Chem. 2010; 391(2-3):197-205. Malkin D et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992; 326(20):1309-15. Monti P et al. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Cancer Res. 2007; 13(13):3789-95. Monti P et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011; 9(3):271-9. Schlegelberger B et al. A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. Pediatr Blood Cancer. 2015; 62(8):1481-4. Scian M et al. Modulation of gene expression by tumor-derived p53 mutants. Cancer Res. 2004; 64(20):7447-54. Siddiqui R et al. The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. Fam Cancer. 2005; 4(2):177-81. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Zerdoumi Y et al. Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. Hum Mutat. 2013; 34(3):453-61.
Comment:
DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.818G>A, in exon 8 that results in an amino acid change, p.Arg273His. This sequence change has been described in the gnomAD database with a low global population frequency of 0.01% (dbSNP rs28934576). This pathogenic sequence change has previously been described in multiple patients and families with Li Fraumeni syndrome (PMIDs: 1565144, 21054160, 25584008). The p.Arg273His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg273 amino acid residue has multiple other amino acid substitutions that are reported to be pathogenic, including p.Arg273Leu, p.Arg273Gly, p.Arg273Ser, and p.Arg273Cys (PMIDs: 10864200, 8425176, 8164043, 8479749). Functional assays demonstrate that the p.Arg273His change results in deficient transactivation activity and results in a dominant negative effect over wild-type p53 (PMIDs: 12826609, 17636407). The p.Arg273His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Comment:
The c.818G>A (p.Arg273His) variant of the TP53 gene replaces arginine with histidine at codon 273 of the TP53 protein. This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, it has been observed as a de novo variant in a proband with breast cancer at age 29 (PMID: 12672316). This variant is within a codon that is an established mutational hotspot in the TP53 gene (PMID: 2046748). Functional studies have shown that the variant results in non-functional of the protein (PMID: 12826609) and evidence of a dominant negative effect and loss of function (PMID: 30224644). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (a BayesDel score > 0.16 and Align-GVGD is C25). Based on the supporting evidence, the c.818G>A (p.Arg273His) variant in TP53 is interpreted as pathogenic.
Comment:
The p.Arg273His variant in TP53 has been reported in at least 6 individuals with Li-Fraumeni syndrome and as a de novo occurence in an individual with breast cancer (selected publications Wong 2006 PMID: 16401470, Khayat 2004 PMID: 15390294, Varley 1997 PMID: 9242456, Chompret 2000 PMID: 10864200, Malkin 1992 PMID: 1565144, Flaman 1995 PMID: 7732013, Lalloo 2003 PMID: 12672316) and it was classified as pathogenic on August 28, 2019 by the ClinGen-approved ClinGen TP53 Variant Curation Expert Panel (Variation ID 12366). It has also been identified in 2/68014 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is within a codon that is an established hotspot in the TP53 gene (Levine 1991 PMID: 2046748). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro transactivation assays show a low functioning allele and there is evidence of a dominant negative effect and loss of function (Kato 2003 PMID: 12826609, Giacomelli 2018 PMID: 30224644). In summary, the p.Arg273His meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PS2, PM2_Supporting.
Comment:
The following ACMG criteria was used: PS4_VS, PS2, PM2_SUP, PS3, PP4_MOD, PM1, PP3
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 273 of the TP53 protein (p.Arg273His). 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 missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (LFS) (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12366). 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: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 273 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 the mutant protein to be non-functional in transactivation assays (IARC database, PMID: 12826609, 20407015, 25584008) and cell growth assays (PMID: 24677579, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 1565144, 7732013, 10864200, 15390294, 16401470, 27374712) and in individuals meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 9242456, 25584008, 25787918). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change replaces Arginine with Histidine at codon 273 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and histidine (Grantham Score 29). There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934576, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 17540308, 1565144, 20693561). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels(PMID: 12826609). In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID: 12366)
Comment:
The c.818G>A, p.Arg273His missense variant in TP53 has been reported in several individuals meeting classic Li-Fraumeni or Chompret criteria,occurring de novo in at least one individual and segregating with disease in affected families (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135). This variant is located in the DNA-binding domain of the TP53 protein and is defined as a contact mutation that eliminates an essential DNA contact (PMID: 20516128). A mutant mouse model for this variant develops various tumors and carcinomas by recapitulating LFS (PMID: 15607980). In addition, experimental studies have shown that this variant disrupts transcriptional activity in yeast-based assays (PMID: 12826609) and enhances cell proliferation, invasion, migration, and drug resistance in vitro (PMID:17636407, 24677579). This variant has three heterozygous alleles in the gnomAD v3.1.1 database, suggesting it is not a common benign variant in the populations represented in this database. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, this variant is classified as pathogenic.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Monti 2011, Wasserman 2015, Kotler 2018); This variant is associated with the following publications: (PMID: 23334668, 20128691, 7732013, 10864200, 18511570, 25896519, 23484829, 29324801, 32039725, 15492269, 17606709, 22811390, 23559009, 22899716, 24573247, 24677579, 25958320, 26703669, 17636407, 25433984, 26332594, 8423216, 20693561, 21054160, 1565144, 21552135, 21484931, 25584008, 23172776, 17540308, 27798748, 25530302, 27498048, 27323394, 27287813, 27346245, 27659839, 27374712, 28091804, 27501770, 25787918, 1447251, 9242456, 12672316, 16401470, 28509937, 20522432, 27831900, 26225655, 26681312, 28453743, 21761402, 16096528, 29489754, 28472496, 21343334, 26585234, 28861920, 29752822, 15607980, 30287823, 30720243, 30092803, 30840781, 31159747, 15951970, 22851211, 28369373, 31105275, 32475984, 32156018, 33300245, 34308366, 32817165, 33372952, 31958074, 33332384, 33245408, 32427313, 33087929, 33144694, 29979965, 15510160)
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9399838]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 14743206, 19454241, 24677579]. This variant is expected to disrupt protein structure [PMID: 24677579, Myriad internal data].
Comment:
Variant summary: TP53 c.818G>A (p.Arg273His) results in a non-conservative amino acid change located in the p53, DNA-binding domain 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 1.6e-05 in 251054 control chromosomes. c.818G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Bougeard_2015, Varley_1997, Wasserman_2015). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.817C>T, p.Arg273Cys), supporting the critical relevance of codon 273 to TP53 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishing TP53 binding (Wasserman_2015) and functional inactiviation (Lang_2004). The following publications have been ascertained in the context of this evaluation (PMID: 25584008, 26014290, 9242456, 15607981). ClinVar contains an entry for this variant (Variation ID: 12366). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The TP53 c.818G>A (p.Arg273His) missense change a maximum founder subpopulation frequency of 0.01% and a maximum non-founder 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: 10645809, 10864200, 16401470, 22851211, 25787918, internal data). Computational evidence supports a deleterious effect of this variant on protein function. Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID: 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
The p.R273H pathogenic mutation (also known as c.818G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 818. The arginine at codon 273 is replaced by histidine, an amino acid with highly similar properties. This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including soft tissue and osteosarcomas, breast cancer, and central nervous system malignancies (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum. Mutat. 2007 Jun;28(6):622-9). In addition, 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). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and 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 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012366 /PMID: 1565144) and different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser / ClinVar ID: VCV000043594, VCV000231060, VCV000376655, VCV000376656, VCV000634682 /PMID: 10864200, 11180592, 8164043, 8425176, 8479749) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 12672316). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10864200, 15390294, 1565144, 16401470, 7732013, 9242456). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The TP53 p.Arg273His variant was identified in 2 of 942 proband chromosomes (frequency: 0.002) from individuals or families with Li Fraumeni Syndrome or thyroid cancer (Masciari 2011, Romei 2017) and reported in multiple case studies in individuals or families with Li-Fraumeni Syndrome (Bemis 2007, Sugawara 2011, Baumuller 2010). In addition, the variant was reported as a somatic mutation in breast cancer, colorectal cancer, non-small cell lung cancer or high-grade glioma tissues (Jiang 2018, Heath-2018, Li 2018). The variant was also identified in dbSNP (ID: rs28934576) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and eight other submitters; as likely pathogenic by two submitters), and in LOVD 3.0 (2x as pathogenic). The variant was identified in control databases in 4 of 245868 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111470 chromosomes (freq: 0.00003), Ashkenazi Jewish in 1 of 9842 chromosomes (freq: 0.0001), but not in the African, Other, Latino, East Asian, Finnish, or South Asian populations. Several functional studies suggests the variant enhances cell migration, invasion abilities, influences apoptosis, leads to more aggressive phenotypes, and enhances cancer cell malignancy (Kang 2018, Joerger 2010, Dong 2007, Li 2014). The p.Arg273 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
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.
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. |
Comment:
The NM_000546.6: c.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, SCV000186052.8). This variant has an allele frequency of 0.00001186 (14/1179946 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed 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: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 ). Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) 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). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PS2, PM2_Supporting, PS3, PP4_Moderate, PM1, PP3. (Bayesian Points: 22; VCEP specifications version 2.0; 7/24/2024).
Comment:
The TP53 c.818G>A, p.Arg273His variant (rs28934576), has been reported in multiple patients diagnosed with Li-Fraumeni syndrome (Curry 2011, Khayat 2004, Malkin 1992, Park 2016, Schlegelberger 2015, Siddiqui 2005, Tsaousis 2019, Zerdoumi 2012). Functional characterization of the variant protein indicates a defect in the transactivation of TP53 targets (Malcikova 2010, Monti 2007, Monti 2011, Zerdoumi 2012) and repression of genes involved in cell proliferation (Scian 2004). This results in an increase in growth, invasiveness, and resistance to apoptosis of cell lines upon DNA damage (Kalo 2012, Li 2014). This variant is found in the general population with an allele frequency of 0.0016% (4/251054 alleles) in the Genome Aggregation Database. The arginine at residue 273 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.868). Based on the above information, the variant is classified as pathogenic. References: Curry S et al. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation. Pediatr Dev Pathol. 2011; 14(3):248-51. Kalo E et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci. 2012; 125(Pt 22):5578-86. Khayat C et al. Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatr Blood Cancer. 2004; 43(6):683-6. Li J et al. Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy. Hum Mutat. 2014; 35(5):575-84. Malcikova J et al. Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. Biol Chem. 2010; 391(2-3):197-205. Malkin D et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992; 326(20):1309-15. Monti P et al. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Cancer Res. 2007; 13(13):3789-95. Monti P et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011; 9(3):271-9. Schlegelberger B et al. A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. Pediatr Blood Cancer. 2015; 62(8):1481-4. Scian M et al. Modulation of gene expression by tumor-derived p53 mutants. Cancer Res. 2004; 64(20):7447-54. Siddiqui R et al. The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. Fam Cancer. 2005; 4(2):177-81. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Zerdoumi Y et al. Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. Hum Mutat. 2013; 34(3):453-61.
Comment:
DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.818G>A, in exon 8 that results in an amino acid change, p.Arg273His. This sequence change has been described in the gnomAD database with a low global population frequency of 0.01% (dbSNP rs28934576). This pathogenic sequence change has previously been described in multiple patients and families with Li Fraumeni syndrome (PMIDs: 1565144, 21054160, 25584008). The p.Arg273His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg273 amino acid residue has multiple other amino acid substitutions that are reported to be pathogenic, including p.Arg273Leu, p.Arg273Gly, p.Arg273Ser, and p.Arg273Cys (PMIDs: 10864200, 8425176, 8164043, 8479749). Functional assays demonstrate that the p.Arg273His change results in deficient transactivation activity and results in a dominant negative effect over wild-type p53 (PMIDs: 12826609, 17636407). The p.Arg273His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Comment:
The c.818G>A (p.Arg273His) variant of the TP53 gene replaces arginine with histidine at codon 273 of the TP53 protein. This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, it has been observed as a de novo variant in a proband with breast cancer at age 29 (PMID: 12672316). This variant is within a codon that is an established mutational hotspot in the TP53 gene (PMID: 2046748). Functional studies have shown that the variant results in non-functional of the protein (PMID: 12826609) and evidence of a dominant negative effect and loss of function (PMID: 30224644). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (a BayesDel score > 0.16 and Align-GVGD is C25). Based on the supporting evidence, the c.818G>A (p.Arg273His) variant in TP53 is interpreted as pathogenic.
Comment:
The p.Arg273His variant in TP53 has been reported in at least 6 individuals with Li-Fraumeni syndrome and as a de novo occurence in an individual with breast cancer (selected publications Wong 2006 PMID: 16401470, Khayat 2004 PMID: 15390294, Varley 1997 PMID: 9242456, Chompret 2000 PMID: 10864200, Malkin 1992 PMID: 1565144, Flaman 1995 PMID: 7732013, Lalloo 2003 PMID: 12672316) and it was classified as pathogenic on August 28, 2019 by the ClinGen-approved ClinGen TP53 Variant Curation Expert Panel (Variation ID 12366). It has also been identified in 2/68014 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is within a codon that is an established hotspot in the TP53 gene (Levine 1991 PMID: 2046748). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro transactivation assays show a low functioning allele and there is evidence of a dominant negative effect and loss of function (Kato 2003 PMID: 12826609, Giacomelli 2018 PMID: 30224644). In summary, the p.Arg273His meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PS2, PM2_Supporting.
Comment:
The following ACMG criteria was used: PS4_VS, PS2, PM2_SUP, PS3, PP4_MOD, PM1, PP3
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 273 of the TP53 protein (p.Arg273His). 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 missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (LFS) (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12366). 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: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 273 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 the mutant protein to be non-functional in transactivation assays (IARC database, PMID: 12826609, 20407015, 25584008) and cell growth assays (PMID: 24677579, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 1565144, 7732013, 10864200, 15390294, 16401470, 27374712) and in individuals meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 9242456, 25584008, 25787918). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change replaces Arginine with Histidine at codon 273 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and histidine (Grantham Score 29). There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934576, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 17540308, 1565144, 20693561). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels(PMID: 12826609). In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID: 12366)
Comment:
The c.818G>A, p.Arg273His missense variant in TP53 has been reported in several individuals meeting classic Li-Fraumeni or Chompret criteria,occurring de novo in at least one individual and segregating with disease in affected families (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135). This variant is located in the DNA-binding domain of the TP53 protein and is defined as a contact mutation that eliminates an essential DNA contact (PMID: 20516128). A mutant mouse model for this variant develops various tumors and carcinomas by recapitulating LFS (PMID: 15607980). In addition, experimental studies have shown that this variant disrupts transcriptional activity in yeast-based assays (PMID: 12826609) and enhances cell proliferation, invasion, migration, and drug resistance in vitro (PMID:17636407, 24677579). This variant has three heterozygous alleles in the gnomAD v3.1.1 database, suggesting it is not a common benign variant in the populations represented in this database. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, this variant is classified as pathogenic.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Monti 2011, Wasserman 2015, Kotler 2018); This variant is associated with the following publications: (PMID: 23334668, 20128691, 7732013, 10864200, 18511570, 25896519, 23484829, 29324801, 32039725, 15492269, 17606709, 22811390, 23559009, 22899716, 24573247, 24677579, 25958320, 26703669, 17636407, 25433984, 26332594, 8423216, 20693561, 21054160, 1565144, 21552135, 21484931, 25584008, 23172776, 17540308, 27798748, 25530302, 27498048, 27323394, 27287813, 27346245, 27659839, 27374712, 28091804, 27501770, 25787918, 1447251, 9242456, 12672316, 16401470, 28509937, 20522432, 27831900, 26225655, 26681312, 28453743, 21761402, 16096528, 29489754, 28472496, 21343334, 26585234, 28861920, 29752822, 15607980, 30287823, 30720243, 30092803, 30840781, 31159747, 15951970, 22851211, 28369373, 31105275, 32475984, 32156018, 33300245, 34308366, 32817165, 33372952, 31958074, 33332384, 33245408, 32427313, 33087929, 33144694, 29979965, 15510160)
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9399838]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 14743206, 19454241, 24677579]. This variant is expected to disrupt protein structure [PMID: 24677579, Myriad internal data].
Comment:
Variant summary: TP53 c.818G>A (p.Arg273His) results in a non-conservative amino acid change located in the p53, DNA-binding domain 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 1.6e-05 in 251054 control chromosomes. c.818G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Bougeard_2015, Varley_1997, Wasserman_2015). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.817C>T, p.Arg273Cys), supporting the critical relevance of codon 273 to TP53 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishing TP53 binding (Wasserman_2015) and functional inactiviation (Lang_2004). The following publications have been ascertained in the context of this evaluation (PMID: 25584008, 26014290, 9242456, 15607981). ClinVar contains an entry for this variant (Variation ID: 12366). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The TP53 c.818G>A (p.Arg273His) missense change a maximum founder subpopulation frequency of 0.01% and a maximum non-founder 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: 10645809, 10864200, 16401470, 22851211, 25787918, internal data). Computational evidence supports a deleterious effect of this variant on protein function. Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID: 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
The p.R273H pathogenic mutation (also known as c.818G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 818. The arginine at codon 273 is replaced by histidine, an amino acid with highly similar properties. This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including soft tissue and osteosarcomas, breast cancer, and central nervous system malignancies (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum. Mutat. 2007 Jun;28(6):622-9). In addition, 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). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and 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 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012366 /PMID: 1565144) and different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser / ClinVar ID: VCV000043594, VCV000231060, VCV000376655, VCV000376656, VCV000634682 /PMID: 10864200, 11180592, 8164043, 8425176, 8479749) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 12672316). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10864200, 15390294, 1565144, 16401470, 7732013, 9242456). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The TP53 p.Arg273His variant was identified in 2 of 942 proband chromosomes (frequency: 0.002) from individuals or families with Li Fraumeni Syndrome or thyroid cancer (Masciari 2011, Romei 2017) and reported in multiple case studies in individuals or families with Li-Fraumeni Syndrome (Bemis 2007, Sugawara 2011, Baumuller 2010). In addition, the variant was reported as a somatic mutation in breast cancer, colorectal cancer, non-small cell lung cancer or high-grade glioma tissues (Jiang 2018, Heath-2018, Li 2018). The variant was also identified in dbSNP (ID: rs28934576) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and eight other submitters; as likely pathogenic by two submitters), and in LOVD 3.0 (2x as pathogenic). The variant was identified in control databases in 4 of 245868 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111470 chromosomes (freq: 0.00003), Ashkenazi Jewish in 1 of 9842 chromosomes (freq: 0.0001), but not in the African, Other, Latino, East Asian, Finnish, or South Asian populations. Several functional studies suggests the variant enhances cell migration, invasion abilities, influences apoptosis, leads to more aggressive phenotypes, and enhances cancer cell malignancy (Kang 2018, Joerger 2010, Dong 2007, Li 2014). The p.Arg273 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
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.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer. | Usui Y | The New England journal of medicine | 2023 | PMID: 36988593 |
| Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. | Li H | Journal of the National Cancer Institute | 2021 | PMID: 33372952 |
| Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants. | Fortuno C | Human mutation | 2021 | PMID: 33300245 |
| Identifying sequence variants contributing to hereditary breast and ovarian cancer in BRCA1 and BRCA2 negative breast and ovarian cancer patients. | Jarhelle E | Scientific reports | 2019 | PMID: 31882575 |
| 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 |
| The mutational landscape of accelerated- and blast-phase myeloproliferative neoplasms impacts patient outcomes. | McNamara CJ | Blood advances | 2018 | PMID: 30327374 |
| Mutational processes shape the landscape of TP53 mutations in human cancer. | Giacomelli AO | Nature genetics | 2018 | PMID: 30224644 |
| A Systematic p53 Mutation Library Links Differential Functional Impact to Cancer Mutation Pattern and Evolutionary Conservation. | Kotler E | Molecular cell | 2018 | PMID: 29979965 |
| The landscape of genomic alterations across childhood cancers. | Gröbner SN | Nature | 2018 | PMID: 29489754 |
| 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 |
| Targeted next-generation sequencing of pediatric neuro-oncology patients improves diagnosis, identifies pathogenic germline mutations, and directs targeted therapy. | Kline CN | Neuro-oncology | 2017 | PMID: 28453743 |
| Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. | Döhner H | Blood | 2017 | PMID: 27895058 |
| The impact of TP53 mutations and TP53 deletions on survival varies between AML, ALL, MDS and CLL: an analysis of 3307 cases. | Stengel A | Leukemia | 2017 | PMID: 27680515 |
| TP53 and Decitabine in Acute Myeloid Leukemia and Myelodysplastic Syndromes. | Welch JS | The New England journal of medicine | 2016 | PMID: 27959731 |
| TP53 mutations in newly diagnosed acute myeloid leukemia: Clinicomolecular characteristics, response to therapy, and outcomes. | Kadia TM | Cancer | 2016 | PMID: 27463065 |
| Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome. | Park KJ | Annals of laboratory medicine | 2016 | PMID: 27374712 |
| Genomic Classification and Prognosis in Acute Myeloid Leukemia. | Papaemmanuil E | The New England journal of medicine | 2016 | PMID: 27276561 |
| Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. | Susswein LR | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26681312 |
| 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 |
| Identification of Medically Actionable Secondary Findings in the 1000 Genomes. | Olfson E | PloS one | 2015 | PMID: 26332594 |
| 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 |
| Revisiting Li-Fraumeni Syndrome From TP53 Mutation Carriers. | Bougeard G | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2015 | PMID: 26014290 |
| 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 |
| A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. | Schlegelberger B | Pediatric blood & cancer | 2015 | PMID: 25787918 |
| 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 |
| Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy. | Li J | Human mutation | 2014 | PMID: 24677579 |
| 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 |
| The TP53 website: an integrative resource centre for the TP53 mutation database and TP53 mutant analysis. | Leroy B | Nucleic acids research | 2013 | PMID: 23161690 |
| BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. | Pennington KP | Cancer | 2013 | PMID: 22811390 |
| 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 |
| Early onset HER2-positive breast cancer is associated with germline TP53 mutations. | Melhem-Bertrandt A | Cancer | 2012 | PMID: 21761402 |
| Gastric cancer in individuals with Li-Fraumeni syndrome. | Masciari S | Genetics in medicine : official journal of the American College of Medical Genetics | 2011 | PMID: 21552135 |
| 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 |
| Association of germline or somatic TP53 missense mutation with oncogene amplification in tumors developed in patients with Li-Fraumeni or Li-Fraumeni-like syndrome. | Sugawara W | Genes, chromosomes & cancer | 2011 | PMID: 21484931 |
| Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. | Monti P | Molecular cancer research : MCR | 2011 | PMID: 21343334 |
| Sebaceous gland carcinoma of the eyelid masquerading as a cutaneous horn in Li--Fraumeni syndrome. | Baumüller S | The British journal of ophthalmology | 2011 | PMID: 20693561 |
| The tumor suppressor p53: from structures to drug discovery. | Joerger AC | Cold Spring Harbor perspectives in biology | 2010 | PMID: 20516128 |
| Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation. | Jordan JJ | Molecular cancer research : MCR | 2010 | PMID: 20407015 |
| Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. | Malcikova J | Biological chemistry | 2010 | PMID: 20128691 |
| Evaluation of transcriptional activity of p53 in individual living mammalian cells. | Imagawa T | Analytical biochemistry | 2009 | PMID: 19454241 |
| Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. | Bougeard G | Journal of medical genetics | 2008 | PMID: 18511570 |
| p53 dominant-negative mutant R273H promotes invasion and migration of human endometrial cancer HHUA cells. | Dong P | Clinical & experimental metastasis | 2007 | PMID: 17636407 |
| 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 |
| EGFR-mutant lung adenocarcinoma in a patient with Li-Fraumeni syndrome. | Bemis LT | The Lancet. Oncology | 2007 | PMID: 17540308 |
| Functional analysis and molecular modeling show a preserved wild-type activity of p53(C238Y). | Ferrone M | Molecular cancer therapeutics | 2006 | PMID: 16818505 |
| Prevalence of early onset colorectal cancer in 397 patients with classic Li-Fraumeni syndrome. | Wong P | Gastroenterology | 2006 | PMID: 16401470 |
| The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. | Siddiqui R | Familial cancer | 2005 | PMID: 15951970 |
| 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 |
| Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. | Khayat CM | Pediatric blood & cancer | 2004 | PMID: 15390294 |
| 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 |
| Prediction of pathogenic mutations in patients with early-onset breast cancer by family history. | Lalloo F | Lancet (London, England) | 2003 | PMID: 12672316 |
| A peptide that binds and stabilizes p53 core domain: chaperone strategy for rescue of oncogenic mutants. | Friedler A | Proceedings of the National Academy of Sciences of the United States of America | 2002 | PMID: 11782540 |
| P53 germline mutations in childhood cancers and cancer risk for carrier individuals. | Chompret A | British journal of cancer | 2000 | PMID: 10864200 |
| A database of germline p53 mutations in cancer-prone families. | Sedlacek Z | Nucleic acids research | 1998 | PMID: 9399838 |
| Germ-line mutations of TP53 in Li-Fraumeni families: an extended study of 39 families. | Varley JM | Cancer research | 1997 | PMID: 9242456 |
| A simple p53 functional assay for screening cell lines, blood, and tumors. | Flaman JM | Proceedings of the National Academy of Sciences of the United States of America | 1995 | PMID: 7732013 |
| High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. | Fagin JA | The Journal of clinical investigation | 1993 | PMID: 8423216 |
| 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 |
| Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. | Malkin D | The New England journal of medicine | 1992 | PMID: 1565144 |
| The p53 tumour suppressor gene. | Levine AJ | Nature | 1991 | PMID: 2046748 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8d32df42-16ac-41f2-9bf1-e2b9ce206190 | - | - | - | - |
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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
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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 | RCV000441169.12 |
Submissions - Somatic
|
Oncogenicity
Help
The submitted oncogenicity classification for each SCV record. (Last evaluated) |
Review Status
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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
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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
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the somatic clinical impact, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|---|
|
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: SCV005094393.2
First In ClinVar: Aug 11, 2024 Last updated: Mar 11, 2025 |
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Comment:
The NM_000546.6: c.818G>A variant in TP53 is a missense variant predicted to cause substitution of arginine by histidine at amino acid 273 (p.R273H). This variant has been reported in numerous unrelated probands meeting Classic LFS and Revised Chompret criteria. Based on this evidence, this variant scores 8 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs, 16401470, 15390294, 9242456, 10864200, 1565144, 7732013; SCV000186052.8). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual with an LFS-associated cancer totaling 4 phenotype points (PS2; PMID: 1267231). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, SCV000186052.8). This variant has an allele frequency of 0.00001186 (14/1179946 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting). In vitro assays performed in yeast and/or human cell lines showed 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: 273) of TP53 that is defined as a mutational hotspot by the ClinGen TP53 VCEP (PM1; PMID: 8023157 ). Computational predictor scores (BayesDel = 0.52; Align GVGD = Class 25) 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). In summary, this variant meets the criteria to be classified as pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PS2, PM2_Supporting, PS3, PP4_Moderate, PM1, PP3. (Bayesian Points: 22; VCEP specifications version 2.0; 7/24/2024).
Comment:
The TP53 c.818G>A, p.Arg273His variant (rs28934576), has been reported in multiple patients diagnosed with Li-Fraumeni syndrome (Curry 2011, Khayat 2004, Malkin 1992, Park 2016, Schlegelberger 2015, Siddiqui 2005, Tsaousis 2019, Zerdoumi 2012). Functional characterization of the variant protein indicates a defect in the transactivation of TP53 targets (Malcikova 2010, Monti 2007, Monti 2011, Zerdoumi 2012) and repression of genes involved in cell proliferation (Scian 2004). This results in an increase in growth, invasiveness, and resistance to apoptosis of cell lines upon DNA damage (Kalo 2012, Li 2014). This variant is found in the general population with an allele frequency of 0.0016% (4/251054 alleles) in the Genome Aggregation Database. The arginine at residue 273 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.868). Based on the above information, the variant is classified as pathogenic. References: Curry S et al. Rhabdomyosarcoma-associated renal cell carcinoma: a link with constitutional Tp53 mutation. Pediatr Dev Pathol. 2011; 14(3):248-51. Kalo E et al. Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species. J Cell Sci. 2012; 125(Pt 22):5578-86. Khayat C et al. Rhabdomyosarcoma, osteosarcoma, and adrenocortical carcinoma in a child with a germline p53 mutation. Pediatr Blood Cancer. 2004; 43(6):683-6. Li J et al. Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy. Hum Mutat. 2014; 35(5):575-84. Malcikova J et al. Analysis of the DNA-binding activity of p53 mutants using functional protein microarrays and its relationship to transcriptional activation. Biol Chem. 2010; 391(2-3):197-205. Malkin D et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992; 326(20):1309-15. Monti P et al. Transcriptional functionality of germ line p53 mutants influences cancer phenotype. Clin Cancer Res. 2007; 13(13):3789-95. Monti P et al. Dominant-negative features of mutant TP53 in germline carriers have limited impact on cancer outcomes. Mol Cancer Res. 2011; 9(3):271-9. Schlegelberger B et al. A child with Li-Fraumeni syndrome: Modes to inactivate the second allele of TP53 in three different malignancies. Pediatr Blood Cancer. 2015; 62(8):1481-4. Scian M et al. Modulation of gene expression by tumor-derived p53 mutants. Cancer Res. 2004; 64(20):7447-54. Siddiqui R et al. The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds. Fam Cancer. 2005; 4(2):177-81. Tsaousis GN et al. Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. BMC Cancer. 2019 Jun 3;19(1):535. Zerdoumi Y et al. Drastic effect of germline TP53 missense mutations in Li-Fraumeni patients. Hum Mutat. 2013; 34(3):453-61.
Comment:
DNA sequence analysis of the TP53 gene demonstrated a sequence change, c.818G>A, in exon 8 that results in an amino acid change, p.Arg273His. This sequence change has been described in the gnomAD database with a low global population frequency of 0.01% (dbSNP rs28934576). This pathogenic sequence change has previously been described in multiple patients and families with Li Fraumeni syndrome (PMIDs: 1565144, 21054160, 25584008). The p.Arg273His change affects a highly conserved amino acid residue located in a domain of the TP53 protein that is known to be functional. The p.Arg273 amino acid residue has multiple other amino acid substitutions that are reported to be pathogenic, including p.Arg273Leu, p.Arg273Gly, p.Arg273Ser, and p.Arg273Cys (PMIDs: 10864200, 8425176, 8164043, 8479749). Functional assays demonstrate that the p.Arg273His change results in deficient transactivation activity and results in a dominant negative effect over wild-type p53 (PMIDs: 12826609, 17636407). The p.Arg273His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL).
Comment:
The c.818G>A (p.Arg273His) variant of the TP53 gene replaces arginine with histidine at codon 273 of the TP53 protein. This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, it has been observed as a de novo variant in a proband with breast cancer at age 29 (PMID: 12672316). This variant is within a codon that is an established mutational hotspot in the TP53 gene (PMID: 2046748). Functional studies have shown that the variant results in non-functional of the protein (PMID: 12826609) and evidence of a dominant negative effect and loss of function (PMID: 30224644). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (a BayesDel score > 0.16 and Align-GVGD is C25). Based on the supporting evidence, the c.818G>A (p.Arg273His) variant in TP53 is interpreted as pathogenic.
Comment:
The p.Arg273His variant in TP53 has been reported in at least 6 individuals with Li-Fraumeni syndrome and as a de novo occurence in an individual with breast cancer (selected publications Wong 2006 PMID: 16401470, Khayat 2004 PMID: 15390294, Varley 1997 PMID: 9242456, Chompret 2000 PMID: 10864200, Malkin 1992 PMID: 1565144, Flaman 1995 PMID: 7732013, Lalloo 2003 PMID: 12672316) and it was classified as pathogenic on August 28, 2019 by the ClinGen-approved ClinGen TP53 Variant Curation Expert Panel (Variation ID 12366). It has also been identified in 2/68014 European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is within a codon that is an established hotspot in the TP53 gene (Levine 1991 PMID: 2046748). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In vitro transactivation assays show a low functioning allele and there is evidence of a dominant negative effect and loss of function (Kato 2003 PMID: 12826609, Giacomelli 2018 PMID: 30224644). In summary, the p.Arg273His meets criteria to be classified as pathogenic for autosomal dominant Li-Fraumeni syndrome. ACMG/AMP criteria applied: PM1, PP3, PS3, PS4, PS2, PM2_Supporting.
Comment:
The following ACMG criteria was used: PS4_VS, PS2, PM2_SUP, PS3, PP4_MOD, PM1, PP3
Comment:
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 273 of the TP53 protein (p.Arg273His). 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 missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (LFS) (PMID: 1565144, 9242456, 17540308, 20693561, 21484931, 21552135). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12366). 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: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Comment:
This missense variant replaces arginine with histidine at codon 273 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 the mutant protein to be non-functional in transactivation assays (IARC database, PMID: 12826609, 20407015, 25584008) and cell growth assays (PMID: 24677579, 25584008, 29979965, 30224644). This variant has been reported in individuals affected with classic Li-Fraumeni syndrome (PMID: 1565144, 7732013, 10864200, 15390294, 16401470, 27374712) and in individuals meeting the Chompret criteria for Li-Fraumeni syndrome (PMID: 9242456, 25584008, 25787918). This variant has been identified in 4/251054 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change replaces Arginine with Histidine at codon 273 of the TP53 protein. The arginine residue is highly conserved among species and is located in a functional domain of the protein which interacts with multiple proteins. There is a large physiochemical difference between arginine and histidine (Grantham Score 29). There is a large physiochemical difference between arginine and tryptophan (Grantham Score 101).This variant is present in population databases at a very low frequency ( rs28934576, ExAC 0.02%) and has been reported in multiple individuals and families affected with Li-Fraumeni and Li-Fraumeni-like syndromes (PMID: 17540308, 1565144, 20693561). Algorithms developed to predict the effect of missense changes on protein structure and function suggest that this variant is likely to be damaging to the protein. In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels(PMID: 12826609). In summary, this is a rare sequence change that is expected to affect the TP53 protein and cause disease.The mutation database Clinvar contains entries for this variant (Variation ID: 12366)
Comment:
The c.818G>A, p.Arg273His missense variant in TP53 has been reported in several individuals meeting classic Li-Fraumeni or Chompret criteria,occurring de novo in at least one individual and segregating with disease in affected families (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135). This variant is located in the DNA-binding domain of the TP53 protein and is defined as a contact mutation that eliminates an essential DNA contact (PMID: 20516128). A mutant mouse model for this variant develops various tumors and carcinomas by recapitulating LFS (PMID: 15607980). In addition, experimental studies have shown that this variant disrupts transcriptional activity in yeast-based assays (PMID: 12826609) and enhances cell proliferation, invasion, migration, and drug resistance in vitro (PMID:17636407, 24677579). This variant has three heterozygous alleles in the gnomAD v3.1.1 database, suggesting it is not a common benign variant in the populations represented in this database. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, this variant is classified as pathogenic.
Comment:
Not observed at a significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Monti 2011, Wasserman 2015, Kotler 2018); This variant is associated with the following publications: (PMID: 23334668, 20128691, 7732013, 10864200, 18511570, 25896519, 23484829, 29324801, 32039725, 15492269, 17606709, 22811390, 23559009, 22899716, 24573247, 24677579, 25958320, 26703669, 17636407, 25433984, 26332594, 8423216, 20693561, 21054160, 1565144, 21552135, 21484931, 25584008, 23172776, 17540308, 27798748, 25530302, 27498048, 27323394, 27287813, 27346245, 27659839, 27374712, 28091804, 27501770, 25787918, 1447251, 9242456, 12672316, 16401470, 28509937, 20522432, 27831900, 26225655, 26681312, 28453743, 21761402, 16096528, 29489754, 28472496, 21343334, 26585234, 28861920, 29752822, 15607980, 30287823, 30720243, 30092803, 30840781, 31159747, 15951970, 22851211, 28369373, 31105275, 32475984, 32156018, 33300245, 34308366, 32817165, 33372952, 31958074, 33332384, 33245408, 32427313, 33087929, 33144694, 29979965, 15510160)
Comment:
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9399838]. Functional studies indicate this variant impacts protein function [PMID: 1631137, 14743206, 19454241, 24677579]. This variant is expected to disrupt protein structure [PMID: 24677579, Myriad internal data].
Comment:
Variant summary: TP53 c.818G>A (p.Arg273His) results in a non-conservative amino acid change located in the p53, DNA-binding domain 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 1.6e-05 in 251054 control chromosomes. c.818G>A has been reported in the literature in multiple individuals affected with Li-Fraumeni Syndrome (Bougeard_2015, Varley_1997, Wasserman_2015). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.817C>T, p.Arg273Cys), supporting the critical relevance of codon 273 to TP53 protein function. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in abolishing TP53 binding (Wasserman_2015) and functional inactiviation (Lang_2004). The following publications have been ascertained in the context of this evaluation (PMID: 25584008, 26014290, 9242456, 15607981). ClinVar contains an entry for this variant (Variation ID: 12366). Based on the evidence outlined above, the variant was classified as pathogenic.
Comment:
The TP53 c.818G>A (p.Arg273His) missense change a maximum founder subpopulation frequency of 0.01% and a maximum non-founder 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: 10645809, 10864200, 16401470, 22851211, 25787918, internal data). Computational evidence supports a deleterious effect of this variant on protein function. Transactivation assays show a low functioning allele according to Kato et al., and evidence of loss of function and a dominant negative effect according to Giacomelli et al. (PMID: 12826609, 30224644). This variant is a somatic hotspot variant in tumors according to the Cancer Hotspots database (cancerhotspots.org). In summary, this variant meets criteria to be classified as pathogenic.
Comment:
The p.R273H pathogenic mutation (also known as c.818G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 818. The arginine at codon 273 is replaced by histidine, an amino acid with highly similar properties. This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and is associated with a classic LFS-associated tumor spectrum, including soft tissue and osteosarcomas, breast cancer, and central nervous system malignancies (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum. Mutat. 2007 Jun;28(6):622-9). In addition, 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). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and 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 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Comment:
The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.87; 3Cnet: 0.97). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000012366 /PMID: 1565144) and different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser / ClinVar ID: VCV000043594, VCV000231060, VCV000376655, VCV000376656, VCV000634682 /PMID: 10864200, 11180592, 8164043, 8425176, 8479749) have been previously reported as pathogenic/likely pathogenic with strong evidence. The variant has been previously reported as de novo in a similarly affected individual (PMID: 12672316). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10864200, 15390294, 1565144, 16401470, 7732013, 9242456). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
The TP53 p.Arg273His variant was identified in 2 of 942 proband chromosomes (frequency: 0.002) from individuals or families with Li Fraumeni Syndrome or thyroid cancer (Masciari 2011, Romei 2017) and reported in multiple case studies in individuals or families with Li-Fraumeni Syndrome (Bemis 2007, Sugawara 2011, Baumuller 2010). In addition, the variant was reported as a somatic mutation in breast cancer, colorectal cancer, non-small cell lung cancer or high-grade glioma tissues (Jiang 2018, Heath-2018, Li 2018). The variant was also identified in dbSNP (ID: rs28934576) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics and eight other submitters; as likely pathogenic by two submitters), and in LOVD 3.0 (2x as pathogenic). The variant was identified in control databases in 4 of 245868 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111470 chromosomes (freq: 0.00003), Ashkenazi Jewish in 1 of 9842 chromosomes (freq: 0.0001), but not in the African, Other, Latino, East Asian, Finnish, or South Asian populations. Several functional studies suggests the variant enhances cell migration, invasion abilities, influences apoptosis, leads to more aggressive phenotypes, and enhances cancer cell malignancy (Kang 2018, Joerger 2010, Dong 2007, Li 2014). The p.Arg273 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.
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.
Citations for somatic classification of this variant
Help| Title | 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 |
| The role of TP53 gain-of-function mutation in multifocal glioblastoma. | Olafson LR | Journal of neuro-oncology | 2020 | PMID: 32002804 |
| A dominant-negative effect drives selection of TP53 missense mutations in myeloid malignancies. | Boettcher S | Science (New York, N.Y.) | 2019 | PMID: 31395785 |
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Record last updated Jul 05, 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.