TP53

Chr 17ADSomatic

tumor protein p53

Also known as: BCC7, BMFS5, LFS1, P53, TRP53

NCBI Gene: 7157 ENSG00000141510 UniProt: P04637

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]

Primary Disease Associations & Inheritance

{Adrenocortical carcinoma, pediatric}MIM #202300

{Basal cell carcinoma 7}MIM #614740

{Choroid plexus papilloma}MIM #260500

{Colorectal cancer}MIM #114500

ADSomatic

{Glioma susceptibility 1}MIM #137800

ADSomatic

{Osteosarcoma}MIM #259500

Somatic

Bone marrow failure syndrome 5MIM #618165

Breast cancer, somaticMIM #114480

Hepatocellular carcinoma, somaticMIM #114550

Li-Fraumeni syndromeMIM #151623

Nasopharyngeal carcinoma, somaticMIM #607107

Pancreatic cancer, somaticMIM #260350

UniProtEsophageal cancer

UniProtSquamous cell carcinoma of the head and neck

UniProtLung cancer

UniProtPapilloma of choroid plexus

235

ClinVar variants

Pathogenic / LP

0.53

pLI score

Active trials

Clinical Summary— TP53

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Gene-Disease Validity (ClinGen)

Li-Fraumeni syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.53) — some intolerance to loss-of-function variants.

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ClinVar Variants

83 Pathogenic / Likely Pathogenic· 84 VUS of 235 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.47LOEUF

pLI 0.532

Z-score 3.26

OE 0.20 (0.10–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

0.98Z-score

OE missense 0.82 (0.73–0.92)

192 obs / 234.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.20 (0.10–0.47)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.73–0.92)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07

0≤1.21.6

LoF obs/exp: 4 / 19.5Missense obs/exp: 192 / 234.3Syn Z: -0.54

ClinVar Variant Classifications

235 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic58

Likely Pathogenic25

VUS84

Likely Benign59

Benign7

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	2	11	0	58
Likely Pathogenic	15	4	6	0	25
VUS	11	56	15	2	84
Likely Benign	0	9	26	24	59
Benign	0	3	3	1	7
Conflicting	—				2
Total	71	74	61	27	235

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TP53 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TP53-related Li-Fraumeni syndrome

definitive

ADLoss Of FunctionAbsent Gene Product

Cancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

TUMOR PROTEIN p53; TP53

MIM #191170 · *

{Adrenocortical carcinoma, pediatric}

MIM #202300