Li-Fraumeni syndrome

Summary

Li-Fraumeni syndrome (MONDO:0018875) is a disease caused by TP53 (GenCC Definitive), with 8 cohort genes and 21 clinical trials. The dominant Reactome pathway is Stabilization of p53 (4 cohort genes). Top therapeutic interventions include arsenic trioxide.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: TP53 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 2,588
• Phenotypes (HPO): 35
• Clinical trials: 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	7	United Kingdom	Validated
Point prevalence	1-9 / 100 000	5	United States	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0002664	Neoplasm	Very frequent (80-99%)
HP:0003002	Breast carcinoma	Frequent (30-79%)
HP:0001909	Leukemia	Occasional (5-29%)
HP:0002665	Lymphoma	Occasional (5-29%)
HP:0002669	Osteosarcoma	Occasional (5-29%)
HP:0002859	Rhabdomyosarcoma	Occasional (5-29%)
HP:0002888	Ependymoma	Occasional (5-29%)
HP:0006744	Adrenocortical carcinoma	Occasional (5-29%)
HP:0007378	Neoplasm of the gastrointestinal tract	Occasional (5-29%)
HP:0009592	Astrocytoma	Occasional (5-29%)
HP:0012126	Stomach cancer	Occasional (5-29%)
HP:0012174	Glioblastoma multiforme	Occasional (5-29%)
HP:0030070	Central primitive neuroectodermal tumor	Occasional (5-29%)
HP:0030392	Choroid plexus carcinoma	Occasional (5-29%)
HP:0100006	Neoplasm of the central nervous system	Occasional (5-29%)
HP:0200063	Colorectal polyposis	Occasional (5-29%)
HP:0002861	Melanoma	Very rare (<1-4%)
HP:0002863	Myelodysplasia	Very rare (<1-4%)
HP:0002885	Medulloblastoma	Very rare (<1-4%)
HP:0002890	Thyroid carcinoma	Very rare (<1-4%)
HP:0002894	Neoplasm of the pancreas	Very rare (<1-4%)
HP:0003003	Colon cancer	Very rare (<1-4%)
HP:0004808	Acute myeloid leukemia	Very rare (<1-4%)
HP:0006721	Acute lymphoblastic leukemia	Very rare (<1-4%)
HP:0009726	Renal neoplasm	Very rare (<1-4%)
HP:0010788	Testicular neoplasm	Very rare (<1-4%)
HP:0012125	Prostate cancer	Very rare (<1-4%)
HP:0012189	Hodgkin lymphoma	Very rare (<1-4%)
HP:0012288	Neoplasm of head and neck	Very rare (<1-4%)
HP:0012539	Non-Hodgkin lymphoma	Very rare (<1-4%)
HP:0100526	Neoplasm of the lung	Very rare (<1-4%)
HP:0100605	Neoplasm of the larynx	Very rare (<1-4%)
HP:0100615	Ovarian neoplasm	Very rare (<1-4%)
HP:0100743	Neoplasm of the rectum	Very rare (<1-4%)
HP:0100768	Choriocarcinoma	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Li-Fraumeni syndrome
Mondo ID	MONDO:0018875
MeSH	D016864
OMIM	151623, 609266
Orphanet	524
DOID	DOID:0111503, DOID:3012
ICD-11	1968061860
NCIT	C3476
SNOMED CT	428850001
UMLS	C0085390
MedGen	88399
GARD	0006902
MedDRA	10066795
NORD	1913
Is cancer (heuristic)	no

Also known as: LFS · LFS1 · LFS3 · Li Fraumeni syndrome · Li-Fraumeni familial cancer susceptibility syndrome · Li-Fraumeni syndrome · Li-Fraumeni syndrome caused by mutation in TP53 · sarcoma family syndrome of Li and Fraumeni · sarcoma, breast, leukemia and adrenal gland syndrome · SBLA syndrome · SBLA syndrome (sarcoma, breast, leukemia, and adrenal gland) · TP53 Li-Fraumeni syndrome · TP53-related Li-Fraumeni syndrome

Data availability: 2,588 ClinVar variants · 174 ClinGen variant curations · 5 GenCC gene-disease records · 62 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Li-Fraumeni syndrome

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant nonsyndromic hearing loss, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

164 uncertain significance, 119 pathogenic, 107 likely benign, 97 conflicting classifications of pathogenicity, 39 pathogenic/likely pathogenic, 39 benign/likely benign, 18 likely pathogenic, 16 benign, 1 pathogenic/likely pathogenic/pathogenic, low penetrance

ClinVar	Variant (HGVS)	Gene	Classification	Review
128042	NM_007194.4(CHEK2):c.1100del (p.Thr367fs)	CHEK2	Pathogenic	criteria provided, multiple submitters, no conflicts
140772	NM_007194.4(CHEK2):c.283C>T (p.Arg95Ter)	CHEK2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1376044	NC_000017.10:g.(?7571752)(8135555_?)del	CNTROB	Pathogenic	criteria provided, single submitter
1455106	NC_000017.10:g.(?7578518)(7658855_?)del	DNAH2	Pathogenic	criteria provided, single submitter
100815	NM_000546.6(TP53):c.736A>G (p.Met246Val)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1024056	NM_000546.6(TP53):c.687_695del (p.Thr230_Ile232del)	TP53	Pathogenic	criteria provided, single submitter
1026335	NM_000546.6(TP53):c.476C>A (p.Ala159Asp)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1045295	NM_000546.6(TP53):c.653_655del (p.Val218_Pro219delinsAla)	TP53	Pathogenic	criteria provided, single submitter
1050359	NM_000546.6(TP53):c.731del (p.Gly244fs)	TP53	Pathogenic	criteria provided, single submitter
1052035	NM_000546.6(TP53):c.737_745del (p.Met246_Arg248del)	TP53	Pathogenic	criteria provided, single submitter
1066819	NC_000017.10:g.(?7571752)(7574043_?)del	TP53	Pathogenic	criteria provided, single submitter
1067825	NM_000546.6(TP53):c.509_520del (p.Thr170_Val173del)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067910	NM_000546.6(TP53):c.472C>A (p.Arg158Ser)	TP53	Pathogenic	criteria provided, single submitter
1068484	NM_000546.6(TP53):c.919+1del	TP53	Pathogenic	criteria provided, single submitter
1068801	NM_000546.6(TP53):c.801del (p.Asn268fs)	TP53	Pathogenic	criteria provided, single submitter
1068830	NM_000546.6(TP53):c.872_890dup (p.His297fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
1069164	NC_000017.10:g.(?7571752)(7579912_?)del	TP53	Pathogenic	criteria provided, single submitter
1069165	NC_000017.10:g.(?7579291)(7579404_?)del	TP53	Pathogenic	criteria provided, single submitter
1069225	NM_000546.6(TP53):c.425del (p.Pro142fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
1069253	NM_000546.6(TP53):c.268_269insGCCCCTCCTGGCCCCTGCCCCTGCCCCT (p.Ser90fs)	TP53	Pathogenic	criteria provided, single submitter
1069265	NM_000546.6(TP53):c.403del (p.Cys135fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
1069305	NM_000546.6(TP53):c.702C>G (p.Tyr234Ter)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
1070469	NM_000546.6(TP53):c.205del (p.Ala69fs)	TP53	Pathogenic	criteria provided, multiple submitters, no conflicts
1070690	NM_000546.6(TP53):c.690_702del (p.Ile232fs)	TP53	Pathogenic	criteria provided, single submitter
1070793	NM_000546.6(TP53):c.119dup (p.Met40fs)	TP53	Pathogenic	criteria provided, single submitter
1071474	NM_000546.6(TP53):c.662_666del (p.Glu221fs)	TP53	Pathogenic	criteria provided, single submitter
1071800	NM_000546.6(TP53):c.245del (p.Pro82fs)	TP53	Pathogenic	criteria provided, single submitter
1071812	NM_000546.6(TP53):c.665dup (p.Pro223fs)	TP53	Pathogenic	criteria provided, single submitter
1072141	NM_000546.6(TP53):c.102del (p.Leu35fs)	TP53	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072958	NM_000546.6(TP53):c.1014dup (p.Glu339fs)	TP53	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 40 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
TP53	Definitive	Autosomal dominant	Li-Fraumeni syndrome 1	12
MDM2	Supportive	Autosomal dominant	Li-Fraumeni syndrome	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TP53	Orphanet:1333	Familial pancreatic carcinoma
TP53	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
TP53	Orphanet:1501	Adrenocortical carcinoma
TP53	Orphanet:210159	Adult hepatocellular carcinoma
TP53	Orphanet:251576	Gliosarcoma
TP53	Orphanet:251579	Giant cell glioblastoma
TP53	Orphanet:251899	Choroid plexus carcinoma
TP53	Orphanet:2807	Papilloma of choroid plexus
TP53	Orphanet:293199	Pleomorphic rhabdomyosarcoma
TP53	Orphanet:3318	Essential thrombocythemia
TP53	Orphanet:524	Li-Fraumeni syndrome
TP53	Orphanet:52688	Myelodysplastic syndrome
TP53	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
TP53	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
TP53	Orphanet:668	Osteosarcoma
TP53	Orphanet:67038	B-cell chronic lymphocytic leukemia
TP53	Orphanet:70573	Small cell lung cancer
TP53	Orphanet:96253	Cushing disease
TP53	Orphanet:99756	Alveolar rhabdomyosarcoma
TP53	Orphanet:99757	Embryonal rhabdomyosarcoma
MDM2	Orphanet:524	Li-Fraumeni syndrome
MDM2	Orphanet:99970	Dedifferentiated liposarcoma
MDM2	Orphanet:99971	Well-differentiated liposarcoma
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma
CDKN2A	Orphanet:1333	Familial pancreatic carcinoma
CDKN2A	Orphanet:1501	Adrenocortical carcinoma
CDKN2A	Orphanet:252206	Melanoma and neural system tumor syndrome
CDKN2A	Orphanet:404560	Familial atypical multiple mole melanoma syndrome
CDKN2A	Orphanet:524	Li-Fraumeni syndrome
CDKN2A	Orphanet:585909	B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2)
CDKN2A	Orphanet:618	Familial melanoma
CDKN2A	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
ALOX12B	Orphanet:281122	Self-improving collodion baby
ALOX12B	Orphanet:313	Lamellar ichthyosis
ALOX12B	Orphanet:79394	Congenital ichthyosiform erythroderma
ACADVL	Orphanet:26793	Very long chain acyl-CoA dehydrogenase deficiency

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TP53	HGNC:11998	ENSG00000141510	P04637	Cellular tumor antigen p53	gencc,clinvar
MDM2	HGNC:6973	ENSG00000135679	Q00987	E3 ubiquitin-protein ligase Mdm2	gencc
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
CDKN2A	HGNC:1787	ENSG00000147889	P42771	Cyclin-dependent kinase inhibitor 2A	clinvar
DNAH2	HGNC:2948	ENSG00000183914	Q9P225	Dynein axonemal heavy chain 2	clinvar
CNTROB	HGNC:29616	ENSG00000170037	Q8N137	Centrobin	clinvar
ALOX12B	HGNC:430	ENSG00000179477	O75342	Arachidonate 12-lipoxygenase, 12R-type	clinvar
ACADVL	HGNC:92	ENSG00000072778	P49748	Very long-chain acyl-CoA dehydrogenase, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TP53	Cellular tumor antigen p53	Multifunctional transcription factor that induces cell cycle arrest, DNA repair or apoptosis upon binding to its target DNA sequence.
MDM2	E3 ubiquitin-protein ligase Mdm2	E3 ubiquitin-protein ligase that mediates ubiquitination of p53/TP53, leading to its degradation by the proteasome.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
CDKN2A	Cyclin-dependent kinase inhibitor 2A	Acts as a negative regulator of the proliferation of normal cells by interacting strongly with CDK4 and CDK6.
DNAH2	Dynein axonemal heavy chain 2	As part of the axonemal inner dynein arm complex plays a central role in ciliary beat.
CNTROB	Centrobin	Required for centriole duplication.
ALOX12B	Arachidonate 12-lipoxygenase, 12R-type	Catalyzes the regio and stereo-specific incorporation of a single molecule of dioxygen into free and esterified polyunsaturated fatty acids generating lipid hydroperoxides that can be further reduced to the corresponding hydroxy species.
ACADVL	Very long-chain acyl-CoA dehydrogenase, mitochondrial	Very long-chain specific acyl-CoA dehydrogenase is one of the acyl-CoA dehydrogenases that catalyze the first step of mitochondrial fatty acid beta-oxidation (FAO), breaking down fatty acids into acetyl-CoA and allowing the production of e…

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 2 · Druggable fraction: 0.38

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	3.5×	0.424
Enzyme (other)	2	3.0×	0.424
Transcription factor	2	2.1×	0.424
Scaffold/PPI	1	2.2×	0.474
Other/Unknown	2	0.5×	0.984

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TP53	Transcription factor	no		p53_tumour_suppressor, p53-like_TF_DNA-bd_sf, p53_tetrameristn
MDM2	Transcription factor	no	2.3.2.27	Znf_RING, Znf_RanBP2, SWIB_MDM2_domain
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
CDKN2A	Scaffold/PPI	no		Ankyrin_rpt-contain_sf, Ank_Repeat/CDKN_Inhibitor, Tumor_suppres_ARF
DNAH2	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
CNTROB	Other/Unknown	no		Centrobin
ALOX12B	Enzyme (other)	yes	1.13.11.31	LipOase, PLAT/LH2_dom, LipOase_mml
ACADVL	Enzyme (other)	yes	1.3.8.8	Acyl-CoA_DH_CS, AcylCoA_DH/ox_M, AcylCo_DH/oxidase_C

Expression context

Cohort genes with no expression data: 0.

7 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	3
ganglionic eminence	1
tendon of biceps brachii	1
adrenal tissue	1
calcaneal tendon	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
cervix squamous epithelium	1
parotid gland	1
pituitary gland	1
bronchial epithelial cell	1
bronchus	1
right uterine tube	1
left testis	1
right testis	1
skin of abdomen	1
skin of leg	1
zone of skin	1
apex of heart	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TP53	223	ubiquitous	marker	ventricular zone, ganglionic eminence, tendon of biceps brachii
MDM2	274	ubiquitous	marker	calcaneal tendon, adrenal tissue, ventricular zone
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
CDKN2A	220	ubiquitous	marker	parotid gland, cervix squamous epithelium, pituitary gland
DNAH2	139	tissue_specific	marker	bronchial epithelial cell, right uterine tube, bronchus
CNTROB	239	ubiquitous	marker	left testis, right testis, ventricular zone
ALOX12B	168	broad	yes	skin of leg, skin of abdomen, zone of skin
ACADVL	295	ubiquitous	marker	right adrenal gland cortex, apex of heart, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 5.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TP53	22,736
MDM2	9,892
CDKN2A	9,311
CHEK2	4,795
ACADVL	2,988
CNTROB	1,884
DNAH2	1,556
ALOX12B	1,126

Intra-cohort edges

A	B	Sources
CDKN2A	MDM2	biogrid_interaction, string_interaction
CDKN2A	TP53	string_interaction
CHEK2	MDM2	intact
CHEK2	TP53	intact, string_interaction
MDM2	TP53	biogrid_interaction, intact, string_interaction

Structural data

PDB: 6 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TP53	P04637	313
MDM2	Q00987	147
CHEK2	O96017	38
CDKN2A	P42771	5
ACADVL	P49748	3
DNAH2	Q9P225	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALOX12B	O75342	92.07
CNTROB	Q8N137	67.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 129. Enrichment computed across 8 evidence-associated genes (6 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Stabilization of p53	4	507.6×	4e-09	TP53, CHEK2, CDKN2A, MDM2
Regulation of TP53 Degradation	4	195.2×	1e-07	TP53, CHEK2, CDKN2A, MDM2
SUMOylation of transcription factors	3	285.5×	3e-06	TP53, CDKN2A, MDM2
Regulation of TP53 Activity through Methylation	3	271.9×	3e-06	TP53, CHEK2, MDM2
Oncogene Induced Senescence	3	167.9×	1e-05	TP53, CDKN2A, MDM2
Regulation of TP53 Activity through Phosphorylation	3	58.9×	3e-04	TP53, CHEK2, MDM2
p53-Dependent G1 DNA Damage Response	2	237.9×	4e-04	CDKN2A, MDM2
p53-Dependent G1/S DNA damage checkpoint	2	237.9×	4e-04	CDKN2A, MDM2
Oxidative Stress Induced Senescence	3	45.3×	4e-04	TP53, CDKN2A, MDM2
G1/S DNA Damage Checkpoints	2	223.9×	4e-04	CDKN2A, MDM2
Regulation of TP53 Expression and Degradation	2	173.0×	6e-04	CDKN2A, MDM2
Transcriptional regulation by RUNX3	2	90.6×	0.002	CDKN2A, MDM2
Transcriptional Regulation by VENTX	2	88.5×	0.002	TP53, CDKN2A
Regulation of RUNX3 expression and activity	2	77.7×	0.002	CDKN2A, MDM2
Cellular responses to stress	3	18.4×	0.003	CDKN2A, MDM2, ACADVL
Evasion of Oncogene Induced Senescence Due to p14ARF Defects	1	1903.3×	0.004	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to p14ARF Defects	1	1903.3×	0.004	CDKN2A
Loss of function of TP53 in cancer due to loss of tetramerization ability	1	1903.3×	0.004	TP53
SUMO E3 ligases SUMOylate target proteins	2	59.5×	0.004	CDKN2A, MDM2
SUMOylation	2	54.4×	0.004	CDKN2A, MDM2
Cellular responses to stimuli	3	15.7×	0.004	CDKN2A, MDM2, ACADVL
Signaling by ALK fusions and activated point mutants	2	50.1×	0.004	TP53, MDM2
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	2	48.8×	0.004	TP53, CHEK2
Cellular Senescence	2	45.9×	0.004	CDKN2A, MDM2
Regulation of TP53 Activity	2	44.3×	0.004	CDKN2A, MDM2
Fatty acid metabolism	2	43.8×	0.004	ALOX12B, ACADVL
Regulation of TP53 Expression	1	951.7×	0.004	TP53
Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4	1	951.7×	0.004	CDKN2A
Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4	1	951.7×	0.004	CDKN2A
Defective Intrinsic Pathway for Apoptosis Due to p14ARF Loss of Function	1	951.7×	0.004	CDKN2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
replicative senescence	3	371.7×	1e-05	TP53, CHEK2, CDKN2A
cellular response to gamma radiation	3	225.7×	3e-05	TP53, CHEK2, MDM2
DNA damage response, signal transduction by p53 class mediator	3	134.5×	9e-05	TP53, CHEK2, MDM2
cellular response to UV-C	2	842.6×	1e-04	TP53, MDM2
thymocyte apoptotic process	2	351.1×	6e-04	TP53, CHEK2
cardiac septum morphogenesis	2	300.9×	7e-04	TP53, MDM2
rRNA transcription	2	247.8×	1e-03	TP53, CDKN2A
regulation of protein catabolic process	2	210.7×	0.001	CHEK2, MDM2
response to antibiotic	2	175.5×	0.002	TP53, MDM2
amyloid fibril formation	2	150.5×	0.002	CDKN2A, MDM2
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	2	123.9×	0.002	TP53, CHEK2
regulation of cell cycle	3	28.0×	0.003	TP53, CDKN2A, MDM2
protein stabilization	3	25.1×	0.003	TP53, CHEK2, CDKN2A
protein localization to nucleus	2	87.8×	0.004	CDKN2A, MDM2
protein sumoylation	2	81.0×	0.004	CDKN2A, MDM2
cellular senescence	2	73.9×	0.005	TP53, CDKN2A
protein destabilization	2	72.6×	0.005	CDKN2A, MDM2
negative regulation of helicase activity	1	2106.5×	0.005	TP53
cellular response to vitamin B1	1	2106.5×	0.005	MDM2
cellular response to actinomycin D	1	2106.5×	0.005	TP53
regulation of intrinsic apoptotic signaling pathway by p53 class mediator	1	2106.5×	0.005	TP53
negative regulation of G1 to G0 transition	1	2106.5×	0.005	TP53
response to formaldehyde	1	2106.5×	0.005	MDM2
cellular response to xenobiotic stimulus	2	60.2×	0.005	TP53, CHEK2
cellular response to hydrogen peroxide	2	58.5×	0.005	CDKN2A, MDM2
Ras protein signal transduction	2	51.4×	0.006	TP53, CDKN2A
double-strand break repair	2	50.8×	0.006	TP53, CHEK2
energy derivation by oxidation of organic compounds	1	1053.2×	0.007	ACADVL
nuclear body organization	1	1053.2×	0.007	CDKN2A
positive regulation of mitochondrial membrane permeability	1	1053.2×	0.007	TP53

Therapeutics

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 4

Druggability breadth: 5 of 8 evidence-associated genes (62%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
TP53	NITROFURANTOIN
MDM2	NITROFURANTOIN
CHEK2	NERATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TP53	196	4
CHEK2	30	4
MDM2	14	4
ACADVL	1	2
CDKN2A	0	0
DNAH2	0	0
CNTROB	0	0
ALOX12B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NITROFURANTOIN	4	MDM2, TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MDM2	1,007	Binding:979, Functional:28
TP53	869	Binding:775, ADMET:83, Functional:10, Toxicity:1
CHEK2	690	Binding:687, Functional:2, ADMET:1
CDKN2A	2	Binding:2
ACADVL	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MDM2	2.3.2.27	RING-type E3 ubiquitin transferase
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
ALOX12B	1.13.11.31	arachidonate 12-lipoxygenase
ACADVL	1.3.8.8, 1.3.8.9	long-chain acyl-CoA dehydrogenase, very-long-chain acyl-CoA dehydrogenase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
TP53	869
MDM2	1,007
CHEK2	690

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
NITROFURANTOIN	4	MDM2, TP53
DIOSMIN	4	TP53
VERTEPORFIN	4	TP53
CANDESARTAN CILEXETIL	4	TP53
DIENESTROL	4	TP53
CLOTRIMAZOLE	4	TP53
COLCHICINE	4	TP53
NABUMETONE	4	TP53
SALMETEROL XINAFOATE	4	TP53
AMIODARONE HYDROCHLORIDE	4	TP53
FURAZOLIDONE	4	TP53
AMOXAPINE	4	TP53
RALOXIFENE HYDROCHLORIDE	4	TP53
NICARDIPINE HYDROCHLORIDE	4	TP53
SULCONAZOLE NITRATE	4	TP53
PYRITHIONE ZINC	4	TP53
LACTIC ACID	4	TP53
OXYMETHOLONE	4	TP53
CHLOROXINE	4	TP53
PROPIOLACTONE	4	TP53
CLOMIPRAMINE HYDROCHLORIDE	4	TP53
PHENYL AMINOSALICYLATE	4	TP53
THIORIDAZINE HYDROCHLORIDE	4	TP53
AMITRIPTYLINE HYDROCHLORIDE	4	TP53
ETHOPROPAZINE HYDROCHLORIDE	4	TP53
MECHLORETHAMINE HYDROCHLORIDE	4	TP53
ECONAZOLE NITRATE	4	TP53
TRIFLUPROMAZINE HYDROCHLORIDE	4	TP53
PROCHLORPERAZINE EDISYLATE	4	TP53
DEQUALINIUM CHLORIDE	4	TP53

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	TP53, MDM2, CHEK2
B	Phased (≥1) drug, not yet approved	1	ACADVL
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ALOX12B
E	Difficult family or no structure, no drug	3	CDKN2A, DNAH2, CNTROB

Undrugged target profiles

4 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CDKN2A	2	MDM2
DNAH2	0	—
CNTROB	0	—
ALOX12B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 21.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	18
PHASE3	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01464086	PHASE3	COMPLETED	LIFSCREEN : Evaluation of Whole Body MRI for Early Detection of Cancers in Subjects With P53 Mutation (Li-Fraumeni Syndrome)
NCT06088030	PHASE2	RECRUITING	Arsenic Trioxide Combined With Chemotherapy for the Treatment of p53-mutated Pediatric Cancer
NCT01981525	PHASE1	COMPLETED	A Pilot Study of Metformin in Patients With a Diagnosis of Li-Fraumeni Syndrome
NCT01143454	Not specified	RECRUITING	Characterization of Patients With Uncommon Presentations and/or Uncommon Diseases Associated With the Cardiovascular System
NCT01443468	Not specified	RECRUITING	Clinical and Genetic Studies of Li-Fraumeni Syndrome
NCT02950987	Not specified	ACTIVE_NOT_RECRUITING	Screening With Whole Body MRI For Detection Of Primary Tumors In Children And Adults With Li-Fraumeni Syndrome (LFS) And Other Cancer Predisposition Syndromes
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03176836	Not specified	ENROLLING_BY_INVITATION	Li-Fraumeni Syndrome Imaging Study
NCT04367246	Not specified	RECRUITING	Li-Fraumeni Syndrome/TP53 Biobank
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04982744	Not specified	RECRUITING	Registry of Li Fraumeni and Li Fraumeni Like Syndromes
NCT05126810	Not specified	RECRUITING	Willingness to Participate in a Trial Comparing Standard Genetic Counseling Versus Personalized Genetic Counseling
NCT06523582	Not specified	RECRUITING	Genetic Bases of Neuroendocrine Neoplasms in Mexican Patients
NCT06712095	Not specified	RECRUITING	Video Capsule Examination in Patients With Lynch Syndrome
NCT07005297	Not specified	NOT_YET_RECRUITING	Clinical Genetics Branch Eligibility Screening Survey
NCT00406445	Not specified	COMPLETED	Role of p53 Gene in Metabolism Regulation in Patients With Li-Fraumeni Syndrome
NCT01737255	Not specified	COMPLETED	Magnetic Resonance Imaging Screening in Li Fraumeni Syndrome
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT04966923	Not specified	COMPLETED	Phenotype and Prognosis of Patients With Breast Cancer and Pathogenic Variants of TP53
NCT06163365	Not specified	UNKNOWN	Inherited Cancer Early Diagnosis (ICED) Study
NCT07032922	Not specified	COMPLETED	Exploring How to Adapt an Evidence-Based Mindful Self-Compassion Program for Young Adults With Li-Fraumeni Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ARSENIC TRIOXIDE	4	1