VCV000012366.51 - ClinVar

NM_000546.6(TP53):c.818G>A (p.Arg273His)

Interpretation:: Pathogenic
Review status:: reviewed by expert panel FDA Recognized Database
Submissions:: 56
First in ClinVar:: Apr 8, 2013
Most recent Submission:: Apr 15, 2023
Last evaluated:: Aug 28, 2019
Accession:: VCV000012366.51
Variation ID:: 12366
Description:: single nucleotide variant

NM_000546.6(TP53):c.818G>A (p.Arg273His)

Allele ID

27405

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

17p13.1

Genomic location

17: 7673802 (GRCh38) GRCh38 UCSC

17: 7577120 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_000546.6:c.818G>A MANE Select	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

... more HGVS ... less HGVS

Protein change

R273H, R141H, R234H, R114H

Other names

p.R273H:CGT>CAT

Canonical SPDI

NC_000017.11:7673801:C:T

Functional consequence

Global minor allele frequency (GMAF)

0.00020 (T)

Allele frequency

Trans-Omics for Precision Medicine (TOPMed) 0.00002

1000 Genomes Project 0.00020

Links

ClinGen: CA000434

UniProtKB: P04637#VAR_005995

OMIM: 191170.0020

dbSNP: rs28934576

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Li-Fraumeni syndrome	Pathogenic	4	reviewed by expert panel	Aug 28, 2019	RCV000463420.12
Li-Fraumeni syndrome 1	Pathogenic/Likely pathogenic	7	criteria provided, multiple submitters, no conflicts	Sep 1, 2022	RCV000013163.29
Hereditary cancer-predisposing syndrome	Pathogenic/Likely pathogenic	3	criteria provided, multiple submitters, no conflicts	Aug 24, 2021	RCV000115738.13
not provided	Pathogenic	6	criteria provided, multiple submitters, no conflicts	Apr 29, 2022	RCV000254693.19
Squamous cell carcinoma of the head and neck	Pathogenic	2	criteria provided, single submitter	-	RCV000422097.3
Lung adenocarcinoma	Pathogenic	2	criteria provided, single submitter	Jun 6, 2022	RCV000431361.3
Adrenocortical carcinoma, hereditary Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5 Bone osteosarcoma Carcinoma of pancreas Choroid plexus papilloma Colorectal cancer Familial cancer of breast Glioma susceptibility 1 Hepatocellular carcinoma Li-Fraumeni syndrome 1 Nasopharyngeal carcinoma	Pathogenic	1	criteria provided, single submitter	Mar 14, 2022	RCV002476955.1
Thyroid gland undifferentiated (anaplastic) carcinoma	Pathogenic	1	no assertion criteria provided	Jan 1, 1993	RCV000013164.6
B-cell chronic lymphocytic leukemia	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000424109.2
Gastric adenocarcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000419960.2
Squamous cell lung carcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000418930.2
Prostate adenocarcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000422733.2
Neoplasm of brain	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000424218.2
Pancreatic adenocarcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000439513.2
Acute myeloid leukemia	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000440815.2
Multiple myeloma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000424833.2
Breast neoplasm	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000443907.2
Uterine carcinosarcoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000423826.2
Adrenal cortex carcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000424627.2
Ovarian serous cystadenocarcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000428779.2
Transitional cell carcinoma of the bladder	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000429822.2
Malignant neoplasm of body of uterus	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000430161.2
Malignant melanoma of skin	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000433409.2
Carcinoma of esophagus	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000435547.2
Brainstem glioma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000434044.2
Small cell lung carcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000437210.2
Glioblastoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000436207.2
Neoplasm	Likely pathogenic	1	no assertion criteria provided	Jul 14, 2015	RCV000441169.2
Medulloblastoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000440474.2
Hepatocellular carcinoma	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000444851.2
Neoplasm of the large intestine	Likely pathogenic	1	no assertion criteria provided	May 31, 2016	RCV000444900.2
Neoplasm of ovary	Pathogenic/Likely pathogenic	2	no assertion criteria provided	Mar 19, 2021	RCV000785345.4
Rhabdomyosarcoma	Pathogenic	1	no assertion criteria provided	Sep 1, 2020	RCV001257517.2
Colorectal cancer Multiple myeloma	Pathogenic	1	no assertion criteria provided	Mar 19, 2021	RCV001527470.2
Malignant tumor of breast	Pathogenic	1	no assertion criteria provided	-	RCV001358389.2
Familial cancer of breast	Pathogenic	1	no assertion criteria provided	Mar 19, 2021	RCV001527484.2
Gastric cancer	Pathogenic	1	no assertion criteria provided	Jul 1, 2021	RCV003162246.1

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
TP53		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2836	2931

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Pathogenic (Aug 28, 2019)	reviewed by expert panel (ClinGen TP53 ACMG Specifications v1) 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: SCV001142550.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Publications: PubMed (9) PubMed: 1565144‚ 12826609‚ 7732013‚ 9242456‚ 15390294‚ 10864200‚ 12672316‚ 30224644‚ 16401470 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8d32df42-16ac-41f2-9bf1-e2b9ce206190 Comment: This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > … (more) This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PS4; PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, there is a de novo observation of a proband with breast cancer at age 29 with parental confirmation (PS2; PMID: 12672316). In summary, TP53 c.818G>A; p.Arg273His meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PP3, PS3, PS4, PS2. (less)
Pathogenic (Jan 12, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV001735236.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	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)
Pathogenic (Mar 18, 2021)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) 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)
Pathogenic (Sep 01, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: yes Allele origin: germline	3billion Accession: SCV002572762.1 First in ClinVar: Sep 17, 2022 Last updated: Sep 17, 2022	Publications: PubMed (9) PubMed: 9242456‚ 12672316‚ 15390294‚ 7732013‚ 30224644‚ 12826609‚ 10864200‚ 16401470‚ 1565144 Comment: The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). It is located in a mutational hot … (more) The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). It 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: 1.00). 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). Different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043594 , VCV000231060 , VCV000376655 , VCV000376656 , VCV000634682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. (less) Clinical Features: Osteosarcoma (present) Zygosity: 1 Single Heterozygote
Pathogenic (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) 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
Likely pathogenic (Feb 22, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Li-Fraumeni syndrome 1 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000677727.2 First in ClinVar: Oct 19, 2014 Last updated: Dec 24, 2022	Publications: PubMed (12) PubMed: 20128691‚ 21552135‚ 21761402‚ 22811390‚ 17606709‚ 18511570‚ 25787918‚ 1565144‚ 21343334‚ 24677579‚ 27374712‚ 15390294
Pathogenic (Jun 06, 2022)	criteria provided, single submitter (AMP Guidelines, 2017) 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
Pathogenic (Apr 29, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) 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)
Pathogenic (Feb 09, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697450.1 First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017	Publications: PubMed (3) PubMed: 9242456‚ 25584008‚ 22899716 Comment: Variant summary: The TP53 c.818G>A (p.Arg273His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. … (more) Variant summary: The TP53 c.818G>A (p.Arg273His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/114148 control chromosomes at a frequency of 0.0000263, which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). The variant has been reported in numerous affected individuals in the literature and the codon location is a known hotspot mutation occurring as a frequent mutation in affected individuals. Functional studies report a dominant negative affect of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Likely pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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)
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001450494.1 First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020	Publications: PubMed (1) PubMed: 30816478 Age: 50-59 years Sex: male Geographic origin: Sri Lanka
Pathogenic (Dec 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) 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	Publications: PubMed (1) PubMed: 28873162
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) 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: SCV001762058.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Clinical Features: Breast carcinoma (present) Sex: female
Pathogenic (Apr 26, 2017)	criteria provided, single submitter (Quest Diagnostics criteria) 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	Publications: PubMed (10) PubMed: 9242456‚ 21484931‚ 17540308‚ 1565144‚ 20693561‚ 21552135‚ 20516128‚ 12826609‚ 17636407‚ 24677579
Pathogenic (Nov 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) 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)	criteria provided, single submitter (ACMG Guidelines, 2015) 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)
Pathogenic (Aug 24, 2021)	criteria provided, single submitter (Ambry General Variant Classification Scheme_2022) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000186052.8 First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022	Publications: PubMed (9) PubMed: 1565144‚ 25584008‚ 26332594‚ 26681312‚ 28453743‚ 29489754‚ 30224644‚ 31882575‚ 9242456 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). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS and has segregated with disease in all families with multiple informative relatives tested (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 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less) Number of individuals with the variant: 1
Pathogenic (Sep 10, 2021)	criteria provided, single submitter (NYGC Assertion Criteria 2020) 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	Publications: PubMed (7) PubMed: 9242456‚ 21484931‚ 17540308‚ 1565144‚ 20693561‚ 21552135‚ 15607980 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) Zygosity: 1 Single Heterozygote Secondary finding: yes
Pathogenic (Mar 14, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Familial cancer of breast Colorectal cancer Hepatocellular carcinoma Glioma susceptibility 1 Li-Fraumeni syndrome 1 Adrenocortical carcinoma, hereditary Bone osteosarcoma Carcinoma of pancreas Choroid plexus papilloma Nasopharyngeal carcinoma Basal cell carcinoma, susceptibility to, 7 Bone marrow failure syndrome 5 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611327.2 First in ClinVar: Nov 11, 2017 Last updated: Dec 31, 2022
Pathogenic (Oct 25, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Li-Fraumeni syndrome Affected status: unknown Allele origin: germline	Invitae Accession: SCV000545317.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 07, 2023	Publications: PubMed (10) PubMed: 28492532‚ 1565144‚ 9242456‚ 17540308‚ 20693561‚ 21484931‚ 21552135‚ 12826609‚ 29979965‚ 30224644 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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. 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)
Pathogenic (Jan 01, 1993)	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	Publications: PubMed (2) PubMed: 1565144‚ 8423216 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)
Pathogenic (Jan 01, 1993)	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	Publications: PubMed (2) PubMed: 1565144‚ 8423216 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)
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Acute myeloid leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504664.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (4) PubMed: 24381225‚ 24641375‚ 24487413‚ 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Prostate adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504665.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504666.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Hepatocellular carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504667.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of brain (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504668.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Brainstem glioma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504669.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504670.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Multiple myeloma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504671.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Carcinoma of esophagus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504672.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Breast neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504673.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (3) PubMed: 9569050‚ 16489069‚ 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Adrenal cortex carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504674.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Glioblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504675.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504676.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Ovarian serous cystadenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504677.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Small cell lung carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504678.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504679.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Transitional cell carcinoma of the bladder (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504680.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Medulloblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504681.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	B-cell chronic lymphocytic leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504682.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504683.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (Jul 14, 2015)	no assertion criteria provided Method: literature only	Neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504684.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Uterine carcinosarcoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504685.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Pathogenic (-)	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
Pathogenic (Sep 01, 2020)	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	Publications: PubMed (1) PubMed: 33372952
Pathogenic (Jul 24, 2014)	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	Publications: PubMed (6) PubMed: 17606709‚ 18511570‚ 15951970‚ 15390294‚ 1565144‚ 23161690
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Pancreatic adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504661.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504662.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant neoplasm of body of uterus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000504663.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A
Likely pathogenic (Dec 01, 2018)	no assertion criteria provided Method: research	Neoplasm of ovary 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: Observation 2:
Pathogenic (-)	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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. (less) Number of individuals with the variant: 1
Pathogenic (Mar 19, 2021)	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
Pathogenic (Mar 19, 2021)	no assertion criteria provided Method: clinical testing	Neoplasm of ovary 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
Pathogenic (Mar 19, 2021)	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
Pathogenic (Jul 01, 2021)	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	Publications: PubMed (1) PubMed: 36988593

Comment:

This variant is within a codon that is an established hotspot in the TP53 gene (PM1; PMID: 2046748). This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has been reported in at least 2 probands meeting classic Li-Fraumeni syndrome criteria and 4 probands meeting Chompret criteria (PS4; PMID: 16401470, 15390294, 9242456, 10864200, 1565144, 7732013). Additionally, there is a de novo observation of a proband with breast cancer at age 29 with parental confirmation (PS2; PMID: 12672316). In summary, TP53 c.818G>A; p.Arg273His meets criteria to be classified as pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM1, PP3, PS3, PS4, PS2.

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:

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:

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). It 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: 1.00). 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). Different missense changes at the same codon (p.Arg273Cys, p.Arg273Gly, p.Arg273Leu, p.Arg273Pro, p.Arg273Ser) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000043594 , VCV000231060 , VCV000376655 , VCV000376656 , VCV000634682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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:

Variant summary: The TP53 c.818G>A (p.Arg273His) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant was found in 3/114148 control chromosomes at a frequency of 0.0000263, which does not exceed the estimated maximal expected allele frequency of a pathogenic TP53 variant (0.0000398). The variant has been reported in numerous affected individuals in the literature and the codon location is a known hotspot mutation occurring as a frequent mutation in affected individuals. Functional studies report a dominant negative affect of the variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, 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:

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 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). To date, the p.R273H mutation has been detected in numerous individuals/families satisfying classic criteria for LFS and has segregated with disease in all families with multiple informative relatives tested (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 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). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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:

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). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. 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:

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 laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

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:

Citations for this variant

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
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
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
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
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.	Nykamp K	Genetics in medicine : official journal of the American College of Medical Genetics	2017	PMID: 28492532
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
Germline TP53 Mutation and Clinical Characteristics of Korean Patients With Li-Fraumeni Syndrome.	Park KJ	Annals of laboratory medicine	2016	PMID: 27374712
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
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Identification of Medically Actionable Secondary Findings in the 1000 Genomes.	Olfson E	PloS one	2015	PMID: 26332594
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
Prospective enterprise-level molecular genotyping of a cohort of cancer patients.	MacConaill LE	The Journal of molecular diagnostics : JMD	2014	PMID: 25157968
Mutants TP53 p.R273H and p.R273C but not p.R273G enhance cancer cell malignancy.	Li J	Human mutation	2014	PMID: 24677579
Prognostic significance of TP53 mutations and single nucleotide polymorphisms in acute myeloid leukemia: a case series and literature review.	Zeichner SB	Asian Pacific journal of cancer prevention : APJCP	2014	PMID: 24641375
Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients.	Kihara R	Leukemia	2014	PMID: 24487413
Haploinsufficiency of del(5q) genes, Egr1 and Apc, cooperate with Tp53 loss to induce acute myeloid leukemia in mice.	Stoddart A	Blood	2014	PMID: 24381225
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
Mutant p53R273H attenuates the expression of phase 2 detoxifying enzymes and promotes the survival of cells with high levels of reactive oxygen species.	Kalo E	Journal of cell science	2012	PMID: 22899716
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
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
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
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
The clinical value of somatic TP53 gene mutations in 1,794 patients with breast cancer.	Olivier M	Clinical cancer research : an official journal of the American Association for Cancer Research	2006	PMID: 16489069
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
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
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
P53 germline mutations in childhood cancers and cancer risk for carrier individuals.	Chompret A	British journal of cancer	2000	PMID: 10864200
Mutations in residues of TP53 that directly contact DNA predict poor outcome in human primary breast cancer.	Berns EM	British journal of cancer	1998	PMID: 9569050
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
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
http://docm.genome.wustl.edu/variants/ENST00000269305:c.818G>A	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/8d32df42-16ac-41f2-9bf1-e2b9ce206190	-	-	-	-

Text-mined citations for rs28934576...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 04, 2023

ClinVar Genomic variation as it relates to human health

NM_000546.6(TP53):c.818G>A (p.Arg273His)

NM_000546.6(TP53):c.818G>A (p.Arg273His)

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs28934576...