Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Summary

Familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome (MONDO:0013806) is a cancer with 2 cohort genes (1 CIViC-evidence somatic driver; 408 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 408

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome
Mondo ID	MONDO:0013806
OMIM	614564
Orphanet	313846
UMLS	C3281203
MedGen	482833
GARD	0017413
Is cancer (heuristic)	yes

Also known as: cutaneous telangiectasia and cancer syndrome, familial · familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome · FCTCS

Data availability: 408 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, tumor predisposition syndrome 2, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

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

408 retrieved; paginated sample, class counts are floors:

198 uncertain significance, 132 likely benign, 34 benign/likely benign, 18 conflicting classifications of pathogenicity, 18 benign, 5 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
224559	NM_001184.4(ATR):c.4957C>T (p.Arg1653Ter)	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
376356	NM_001184.4(ATR):c.2320del (p.Ile774fs)	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
938417	NM_001184.4(ATR):c.2320dup (p.Ile774fs)	ATR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3588636	NM_001184.4(ATR):c.1399A>T (p.Lys467Ter)	ATR	Likely pathogenic	criteria provided, single submitter
4081197	NM_001184.4(ATR):c.5261_5264del (p.Thr1754fs)	ATR	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4531210	NM_001184.4(ATR):c.4912del (p.Gln1638fs)	ATR	Likely pathogenic	criteria provided, single submitter
4759334	NM_001184.4(ATR):c.7298del (p.Pro2433fs)	ATR	Likely pathogenic	criteria provided, single submitter
4759335	NM_001184.4(ATR):c.7639C>T (p.Arg2547Ter)	ATR	Likely pathogenic	criteria provided, single submitter
1034823	NM_001184.4(ATR):c.6800T>C (p.Ile2267Thr)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044519	NM_001184.4(ATR):c.2638G>A (p.Ala880Thr)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1394841	NM_001184.4(ATR):c.1258C>G (p.Leu420Val)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1443597	NM_001184.4(ATR):c.3458A>G (p.Asn1153Ser)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157977	NM_001184.4(ATR):c.3424A>G (p.Ser1142Gly)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157980	NM_001184.4(ATR):c.3799G>A (p.Val1267Ile)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157985	NM_001184.4(ATR):c.4351C>T (p.Arg1451Trp)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
157990	NM_001184.4(ATR):c.483A>G (p.Arg161=)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343585	NM_001184.4(ATR):c.6896T>C (p.Met2299Thr)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
343630	NM_001184.4(ATR):c.59+4G>A	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
379486	NM_001184.4(ATR):c.992A>G (p.Asp331Gly)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
513755	NM_001184.4(ATR):c.2704T>C (p.Ser902Pro)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
546281	NM_001184.4(ATR):c.437C>A (p.Thr146Lys)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
805997	NM_001184.4(ATR):c.7349+2T>C	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
845385	NM_001184.4(ATR):c.1359T>G (p.His453Gln)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
899825	NM_001184.4(ATR):c.7817G>A (p.Arg2606Gln)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
900024	NM_001184.4(ATR):c.1904G>A (p.Arg635Gln)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
970736	NM_001184.4(ATR):c.4615G>A (p.Gly1539Ser)	ATR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002078	NM_001184.4(ATR):c.2261C>T (p.Ser754Leu)	ATR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1005744	NM_001184.4(ATR):c.4061G>C (p.Cys1354Ser)	ATR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1006055	NM_001184.4(ATR):c.4730G>T (p.Ser1577Ile)	ATR	Uncertain significance	criteria provided, multiple submitters, no conflicts
1007549	NM_001184.4(ATR):c.3581+5A>G	ATR	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
ANTXR1	LoF	LUNG,MEL,STAD,UTUC	CIViC #524

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
ANTXR1	Moderate	Autosomal dominant	familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	16
ATR	Moderate	Autosomal dominant	familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANTXR1	Orphanet:2067	GAPO syndrome
ATR	Orphanet:313846	Familial cutaneous telangiectasia and oropharyngeal cancer predisposition syndrome
ATR	Orphanet:808	Seckel syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANTXR1	HGNC:21014	ENSG00000169604	Q9H6X2	Anthrax toxin receptor 1	gencc,clinvar
ATR	HGNC:882	ENSG00000175054	Q13535	Serine/threonine-protein kinase ATR	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANTXR1	Anthrax toxin receptor 1	Plays a role in cell attachment and migration.
ATR	Serine/threonine-protein kinase ATR	Serine/threonine protein kinase which activates checkpoint signaling upon genotoxic stresses such as ionizing radiation (IR), ultraviolet light (UV), or DNA replication stalling, thereby acting as a DNA damage sensor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANTXR1	Other/Unknown	no		VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel
ATR	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
decidua	1
palpebral conjunctiva	1
stromal cell of endometrium	1
Brodmann (1909) area 23	1
adrenal tissue	1
epithelium of nasopharynx	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANTXR1	270	ubiquitous	marker	stromal cell of endometrium, decidua, palpebral conjunctiva
ATR	289	ubiquitous	marker	Brodmann (1909) area 23, epithelium of nasopharynx, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATR	3,541
ANTXR1	2,039

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ATR	Q13535	10
ANTXR1	Q9H6X2	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 35. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Uptake and function of anthrax toxins	1	475.8×	0.018	ANTXR1
Diseases of DNA Double-Strand Break Repair	1	407.9×	0.018	ATR
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	407.9×	0.018	ATR
Diseases of DNA repair	1	285.5×	0.018	ATR
Cellular response to heat stress	1	196.9×	0.018	ATR
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.018	ATR
Homology Directed Repair	1	154.3×	0.018	ATR
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.018	ATR
Impaired BRCA2 binding to RAD51	1	154.3×	0.018	ATR
Activation of ATR in response to replication stress	1	150.3×	0.018	ATR
HDR through Single Strand Annealing (SSA)	1	146.4×	0.018	ATR
Meiosis	1	142.8×	0.018	ATR
Fanconi Anemia Pathway	1	139.3×	0.018	ATR
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.018	ATR
DNA Double-Strand Break Repair	1	124.1×	0.019	ATR
Reproduction	1	95.2×	0.021	ATR
HDR through Homologous Recombination (HRR)	1	95.2×	0.021	ATR
TP53 Regulates Transcription of DNA Repair Genes	1	90.6×	0.021	ATR
Meiotic synapsis	1	70.5×	0.024	ATR
Regulation of HSF1-mediated heat shock response	1	69.6×	0.024	ATR
G2/M Checkpoints	1	67.2×	0.024	ATR
Regulation of TP53 Activity	1	66.4×	0.024	ATR
G2/M DNA damage checkpoint	1	60.1×	0.024	ATR
Regulation of TP53 Activity through Phosphorylation	1	58.9×	0.024	ATR
Processing of DNA double-strand break ends	1	57.1×	0.024	ATR
DNA Repair	1	49.2×	0.027	ATR
Cell Cycle Checkpoints	1	44.3×	0.029	ATR
Transcriptional Regulation by TP53	1	31.0×	0.040	ATR
Cellular responses to stress	1	18.4×	0.064	ATR
Cell Cycle	1	18.0×	0.064	ATR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
establishment of RNA localization to telomere	1	4213.0×	0.002	ATR
establishment of protein-containing complex localization to telomere	1	4213.0×	0.002	ATR
positive regulation of telomerase catalytic core complex assembly	1	4213.0×	0.002	ATR
nuclear membrane disassembly	1	2808.7×	0.003	ATR
negative regulation of extracellular matrix assembly	1	2106.5×	0.003	ANTXR1
protein localization to chromosome, telomeric region	1	766.0×	0.006	ATR
response to arsenic-containing substance	1	601.9×	0.006	ATR
regulation of cellular response to heat	1	526.6×	0.006	ATR
positive regulation of DNA damage response, signal transduction by p53 class mediator	1	495.6×	0.006	ATR
replicative senescence	1	495.6×	0.006	ATR
negative regulation of DNA replication	1	443.5×	0.006	ATR
mitotic G2/M transition checkpoint	1	401.2×	0.006	ATR
positive regulation of telomere maintenance via telomerase	1	366.4×	0.007	ATR
cellular response to gamma radiation	1	300.9×	0.007	ATR
regulation of double-strand break repair	1	290.6×	0.007	ATR
nucleobase-containing compound metabolic process	1	263.3×	0.007	ATR
positive regulation of epidermal growth factor receptor signaling pathway	1	247.8×	0.007	ANTXR1
interstrand cross-link repair	1	216.1×	0.008	ATR
replication fork processing	1	210.7×	0.008	ATR
DNA damage checkpoint signaling	1	195.9×	0.008	ATR
blood vessel development	1	187.2×	0.008	ANTXR1
substrate adhesion-dependent cell spreading	1	172.0×	0.008	ANTXR1
response to mechanical stimulus	1	150.5×	0.009	ATR
cellular response to UV	1	147.8×	0.009	ATR
telomere maintenance	1	133.8×	0.009	ATR
double-strand break repair	1	101.5×	0.012	ATR
DNA replication	1	82.6×	0.014	ATR
actin cytoskeleton organization	1	39.6×	0.028	ANTXR1
response to xenobiotic stimulus	1	34.5×	0.031	ATR
DNA repair	1	31.9×	0.032	ATR

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATR	8	3
ANTXR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERALASERTIB	3	ATR
DACTOLISIB	3	ATR
BERZOSERTIB	2	ATR
CAMONSERTIB	2	ATR
TUVUSERTIB	2	ATR
ELIMUSERTIB	1	ATR
M4344	1	ATR
AEW-541	1	ATR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ATR	231	Binding:226, Functional:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATR	2.7.11.1	non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ATR	231

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

8 approved/phased drugs hit cohort targets but don’t yet appear in disease-level clinical trials. Target-inhibition rationale is strongest for cancer driver genes; a bioactivity hit is a screening signal, not a treatment claim.

Compound	Max phase	Cohort target (bioactivity)
CERALASERTIB	3	ATR
DACTOLISIB	3	ATR
BERZOSERTIB	2	ATR
CAMONSERTIB	2	ATR
TUVUSERTIB	2	ATR
ELIMUSERTIB	1	ATR
M4344	1	ATR
AEW-541	1	ATR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ATR
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ANTXR1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ANTXR1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.