NM_000546.6:c.818G>A

Variant names:

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

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 26 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_Very_StrongO3_ModerateO4_ModerateO5_SupportingO6_SupportingO7_Strong

The NM_000546.6(TP53):c.818G>A (p.Arg273His) variant causes a missense change involving the alteration of a conserved nucleotide. The gene TP53 is a tumor suppressor gene (CancerMine: 1768 TSG, 396 oncogene, 578 driver citations). The gene TP53 is a known oncogene (CancerMine: 1768 TSG, 396 oncogene, 578 driver citations). The gene TP53 is a cancer driver gene (CancerMine: 1768 TSG, 396 oncogene, 578 driver citations). 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. The variant has been observed in cBioPortal in 3303 samples across 207 studies and 220 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). 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 ACGS-UK Somatic Oncogenicity v2025

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 26 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		Variant on SVIG-UK Canonical Variants List — Stand-alone Oncogenic (O1); ClinVar oncogenic/SCI T1 (expert panel/practice guideline, ★★★+) — Very Strong (O1); ClinVar oncogenic/SCI T1 (multiple submitters, ★★) — Strong (O1); ClinVar oncogenic/SCI T1 (single/no review, ★0–1) — Moderate (O1); TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (16.0 pts): SVIG-UK Canonical Variants List, ClinVar (somatic oncogenic/LO (★★★)), CGI (Cancer Genome Interpreter), ClinVar germline P/LP in TSG (★★★)
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000006, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=3303 | studies=207 | cancer types=220 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts.
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: true | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 6034, same AA change = 862; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 63 pathogenic, 3 benign (OR vs. background: 90.7); Variant does not impact splicing — splice-hotspot path not applicable

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

Submit to ClinVar