TP53 p.Arg273His

Variant names:

• chr17-7673802-C-T
• rs28934576
• NM_000546.6:c.818G>A
• TP53 p.Arg273His

Your query was ambiguous. Multiple possible variants found:

• chr17-7673802-C-T
• chr17-7673801-AC-GT

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 20 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000546.6(TP53):c.818G>A (p.Arg273His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.00000575, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV002572762: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:12826609, 30224644)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R273C: Pathogenic/Likely_pathogenic (ClinVar VariationId 43594, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R273?: Uncertain_significance (ClinVar VariationId 2055104, 1 star); p.R273= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 619925) This variant is listed in the SVIG-UK Canonical Variants List — a curated registry of well-established oncogenic variants (O1 criterion, stand-alone Oncogenic). This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 862 samples carry this exact amino acid change out of 6034 samples with a variant at this residue. This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Li-fraumeni syndrome 1 (lfs1); it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:46 O:6
• Conservation: PhyloP100: 7.91
• Publications: 238 publications found

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 Gene-Disease associations (from GenCC):

• breast cancer

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• Li-Fraumeni syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• Li-Fraumeni syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• adrenocortical carcinoma, hereditary

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
• sarcoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• bone marrow failure syndrome 5

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• colorectal cancer

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• choroid plexus carcinoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACMG Germline Pathogenicity v2019

Specifications for TP53 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 20 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV002572762: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 12826609, 30224644).; SCV002764339: 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).; SCV004043518: Functional studies indicate this variant impacts protein function [PMID: 1631137, 14743206, 19454241, 24677579].; SCV005402346: 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).; SCV000186052: 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).; SCV000821786: "In addition, experimental studies have shown that this variant affects TP53 transactivation activity at variable levels(PMID: 12826609)."; SCV001735236: 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).; SCV000149647: Published functional studies demonstrate a damaging effect: non-functional transactivation, loss of growth suppression activity (Kato 2003, Monti 2011, Wasserman 2015, Kotler 2018); SCV000605425: 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).; SCV002072052: 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).; SCV000545317: Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644).; SCV000697450: The most pronounced variant effect results in abolishing TP53 binding (Wasserman_2015) and functional inactiviation (Lang_2004). PMID: 25584008, 26014290, 9242456, 15607981; SCV001142550: "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)."; SCV004823764: 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).; SCV004848862: 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).; SCV001554107: 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).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 63 pathogenic, 3 benign (OR vs. background: 90.7).
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.00000575 — very rare for AD/XL gene (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R273C: Pathogenic/Likely_pathogenic (ClinVar VariationId 43594, 2 stars); Other variants at the same amino acid residue (not pathogenic): p.R273?: Uncertain_significance (ClinVar VariationId 2055104, 1 star); p.R273= (synonymous): Conflicting_classifications_of_pathogenicity (ClinVar VariationId 619925)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000546.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TP53 NM_000546.6	MANE Select	c.818G>A p.Arg273His	missense	Exon 8 of 11	Prot: NP_000537.3
	TP53 NM_001126112.3		c.818G>A p.Arg273His	missense	Exon 8 of 11	Prot: NP_001119584.1 UniProt:
	TP53 NM_001407262.1		c.818G>A p.Arg273His	missense	Exon 9 of 12	Prot: NP_001394191.1 UniProt:

TP53 NM_000546.6

MANE Select

HGVSc / HGVSpc.818G>Ap.Arg273His

Exon rankExon 8 of 11

missense

Prot: NP_000537.3

TP53 NM_001126112.3

HGVSc / HGVSpc.818G>Ap.Arg273His

Exon rankExon 8 of 11

missense

Prot: NP_001119584.1UniProt: K7PPA8P04637-1

TP53 NM_001407262.1

HGVSc / HGVSpc.818G>Ap.Arg273His

Exon rankExon 9 of 12

missense

Prot: NP_001394191.1UniProt: K7PPA8P04637-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TP53 ENST00000269305.9	TSL:1MANE Select	c.818G>A p.Arg273His	missense	Exon 8 of 11	Prot: ENSP00000269305.4 UniProt:
	TP53 ENST00000445888.6	TSL:1	c.818G>A p.Arg273His	missense	Exon 8 of 11	Prot: ENSP00000391478.2 UniProt:
	TP53 ENST00000610292.4	TSL:1	c.701G>A p.Arg234His	missense	Exon 7 of 10	Prot: ENSP00000478219.1 UniProt:

TP53 ENST00000269305.9

TSL:1MANE Select

HGVSc / HGVSpc.818G>Ap.Arg273His

Exon rankExon 8 of 11

missense

Prot: ENSP00000269305.4UniProt: P04637-1

TP53 ENST00000445888.6

TSL:1

HGVSc / HGVSpc.818G>Ap.Arg273His

Exon rankExon 8 of 11

missense

Prot: ENSP00000391478.2UniProt: P04637-1

TP53 ENST00000610292.4

TSL:1

HGVSc / HGVSpc.701G>Ap.Arg234His

Exon rankExon 7 of 10

missense

Prot: ENSP00000478219.1UniProt: P04637-4

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000197	AC:3	Hom:0	AN:152054	Cov:31
GnomAD2 exomes	AF: 0.0000159	AC:4	Hom:	AN:251054	Cov:
GnomAD4 exome Warning	AF: 0.0000103	AC:15	Hom:0	AN:1461770	Cov:33
GnomAD4 genome Warning	AF: 0.0000197	AC:3	Hom:0	AN:152172	Cov:31
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000472	AC:16	Hom:0	AN:339192	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.00000800	AC:1	Hom:0	AN:122100	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000250	3	120180	0.00000530	1	188550

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
11	-	-	Li-Fraumeni syndrome 1 (11)
10	-	-	Li-Fraumeni syndrome (10)
8	-	-	not provided (8)
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	Ovarian neoplasm (2)
1	-	-	Adrenocortical carcinoma, hereditary (1)
1	-	-	Breast and/or ovarian cancer (1)
1	-	-	Choroid plexus papilloma;C0346153:Familial cancer of breast;C0346629:Colorectal cancer;C0585442:Bone osteosarcoma;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931038:Familial pancreatic carcinoma;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7;C4748488:Bone marrow failure syndrome 5 (1)
1	-	-	Familial cancer of breast (1)
1	-	-	Gastric cancer (1)
1	-	-	Lung adenocarcinoma (1)
1	-	-	Malignant tumor of breast (1)
1	-	-	Multiple myeloma;C0346629:Colorectal cancer (1)
1	-	-	Rhabdomyosarcoma (2)
1	-	-	Squamous cell carcinoma of the head and neck (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-7.5
GPN-Star score	N/A	7.5
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.94	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Uncertain	2.1	M
PhyloP100	Pathogenic	7.9
popEVE	Benign	-3.7
PrimateAI	Uncertain	0.68	T
PromoterAI	N/A	-0.025	Neutral
PROVEAN	Pathogenic	-4.6	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.033	D
Varity_R	N/A	0.85
VESM-3B	Benign	-12

Showing 31 of 31 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

1 no calibration

1 assay found for this variant.

No calibration: 1 assay (score only).

None of these data are clinically calibrated — they are not validated, so interpret them with great caution.

Nucleotide level

Deep mutational scan of human TP53 in HCT116 colorectal cancer cells covering Exons 5, 6, 7 and 8

• Gene: TP53
• Score: 0.887

No calibration data

This score is at approximately the 49th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

dbSNP: rs28934576;

hg19: chr17-7577120;

COSMIC: COSV52660980;

COSMIC: COSV52660980;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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