Tumor predisposition syndrome 3

Summary

Tumor predisposition syndrome 3 (MONDO:0014368) is a cancer caused by POT1 (GenCC Definitive), with 2 cohort genes (1 CIViC-evidence somatic driver; 1,907 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: POT1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 1,907

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	tumor predisposition syndrome 3
Mondo ID	MONDO:0014368
OMIM	615848, 616568
UMLS	C4014476
MedGen	862913
GARD	0018582
Is cancer (heuristic)	yes

Also known as: CMM10 · glioma susceptibility 9 · glioma susceptibility type 9 · GLM9 · malignant glioma caused by mutation in POT1 · melanoma, cutaneous malignant, susceptibility to, 10 · melanoma, cutaneous malignant, susceptibility to, type 10 · POT1 tumor predisposition · POT1-related tumor predisposition syndrome · POT1-TPD

Data availability: 1,907 ClinVar variants · 2 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 › susceptibility to familial cutaneous melanoma › tumor predisposition syndrome 3

Related subtypes (9): melanoma, cutaneous malignant, susceptibility to, 1, melanoma, cutaneous malignant, susceptibility to, 2, melanoma, cutaneous malignant, susceptibility to, 4, melanoma, cutaneous malignant, susceptibility to, 3, melanoma, cutaneous malignant, susceptibility to, 7, melanoma, cutaneous malignant, susceptibility to, 5, melanoma, cutaneous malignant, susceptibility to, 6, melanoma, cutaneous malignant, susceptibility to, 8, melanoma, cutaneous malignant, susceptibility to, 9

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:

275 uncertain significance, 224 likely benign, 42 conflicting classifications of pathogenicity, 34 pathogenic, 14 likely pathogenic, 5 pathogenic/likely pathogenic, 4 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1003943	NM_015450.3(POT1):c.285_286insCT (p.Ile96fs)	POT1	Pathogenic	criteria provided, single submitter
1006038	NM_015450.3(POT1):c.255+1G>T	POT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1025033	NC_000007.13:g.(?124510955)(124537227_?)del	POT1	Pathogenic	criteria provided, single submitter
1035359	NM_015450.3(POT1):c.1414_1415insT (p.Ser472fs)	POT1	Pathogenic	criteria provided, single submitter
1036448	NC_000007.13:g.(?124482851)(124483027_?)del	POT1	Pathogenic	criteria provided, single submitter
1036449	NC_000007.13:g.(?124499001)(124511105_?)del	POT1	Pathogenic	criteria provided, single submitter
1042147	NM_015450.3(POT1):c.1262C>A (p.Ser421Ter)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1045392	NM_015450.3(POT1):c.1030G>T (p.Glu344Ter)	POT1	Pathogenic	criteria provided, single submitter
1052329	NM_015450.3(POT1):c.329dup (p.Leu110fs)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1052949	NM_015450.3(POT1):c.9+4A>G	POT1	Pathogenic	criteria provided, single submitter
1055178	NM_015450.3(POT1):c.1672dup (p.Tyr558fs)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1055219	NM_015450.3(POT1):c.1502_1503del (p.Tyr501fs)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1056550	NM_015450.3(POT1):c.744_745insA (p.Gln249fs)	POT1	Pathogenic	criteria provided, single submitter
1057927	NM_015450.3(POT1):c.777_781del (p.Leu259fs)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1063217	NM_015450.3(POT1):c.873_885del (p.Asp291fs)	POT1	Pathogenic	criteria provided, single submitter
1064274	NC_000007.13:g.(?124486986)(124537227_?)del	POT1	Pathogenic	criteria provided, single submitter
1337751	NM_015450.3(POT1):c.1572G>A (p.Trp524Ter)	POT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1348991	NM_015450.3(POT1):c.631dup (p.His211fs)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1360495	NM_015450.3(POT1):c.562_563del (p.Arg188fs)	POT1	Pathogenic	criteria provided, single submitter
139524	NM_015450.3(POT1):c.818G>T (p.Arg273Leu)	POT1	Pathogenic	no assertion criteria provided
139526	NM_015450.3(POT1):c.1869G>C (p.Gln623His)	POT1	Pathogenic	no assertion criteria provided
1395307	NM_015450.3(POT1):c.1615C>T (p.Gln539Ter)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1428610	NM_015450.3(POT1):c.669C>G (p.Tyr223Ter)	POT1	Pathogenic	criteria provided, single submitter
1439061	NM_015450.3(POT1):c.719del (p.Arg240fs)	POT1	Pathogenic	criteria provided, single submitter
1451603	NM_015450.3(POT1):c.1381_1382del (p.Leu460_Ser461insTer)	POT1	Pathogenic	criteria provided, single submitter
1451887	NM_015450.3(POT1):c.118G>T (p.Gly40Ter)	POT1	Pathogenic	criteria provided, single submitter
1451927	NM_015450.3(POT1):c.1593del (p.Ala532fs)	POT1	Pathogenic	criteria provided, single submitter
1452034	NM_015450.3(POT1):c.279_280del (p.Gln94fs)	POT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1452522	NM_015450.3(POT1):c.1322dup (p.Asn441fs)	POT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453462	NM_015450.3(POT1):c.258dup (p.Gln87fs)	POT1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
POT1	Act	ANGS,CLLSLL,LGGNOS,MEL,SOFT_TISSUE	CIViC #9935

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
POT1	Definitive	Autosomal dominant	tumor predisposition syndrome 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POT1	Orphanet:251627	Oligodendroglioma
POT1	Orphanet:251630	Anaplastic oligodendroglioma
POT1	Orphanet:618	Familial melanoma
POT1	Orphanet:67038	B-cell chronic lymphocytic leukemia
RAG1	Orphanet:157949	Combined immunodeficiency with granulomatosis
RAG1	Orphanet:231154	Combined immunodeficiency due to partial RAG1 deficiency
RAG1	Orphanet:331206	Severe combined immunodeficiency due to complete RAG1/2 deficiency
RAG1	Orphanet:39041	Omenn 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
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	gencc,clinvar
RAG1	HGNC:9831	ENSG00000166349	P15918	V(D)J recombination-activating protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.
RAG1	V(D)J recombination-activating protein 1	Catalytic component of the RAG complex, a multiprotein complex that mediates the DNA cleavage phase during V(D)J recombination.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1
RAG1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS

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
calcaneal tendon	1
germinal epithelium of ovary	1
secondary oocyte	1
buccal mucosa cell	1
male germ line stem cell (sensu Vertebrata) in testis	1
thymus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon
RAG1	164	broad	marker	thymus, buccal mucosa cell, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAG1	3,549
POT1	1,842

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POT1	Q9NUX5	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RAG1	P15918	81.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 16. 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
Telomere C-strand synthesis initiation	1	407.9×	0.013	POT1
Processive synthesis on the C-strand of the telomere	1	380.7×	0.013	POT1
Telomere C-strand (Lagging Strand) Synthesis	1	380.7×	0.013	POT1
Removal of the Flap Intermediate from the C-strand	1	317.2×	0.013	POT1
Telomere Extension By Telomerase	1	228.4×	0.013	POT1
Polymerase switching on the C-strand of the telomere	1	211.5×	0.013	POT1
Interleukin-7 signaling	1	158.6×	0.014	RAG1
Packaging Of Telomere Ends	1	109.8×	0.014	POT1
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.014	POT1
Cleavage of the damaged purine	1	102.0×	0.014	POT1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.014	POT1
Cleavage of the damaged pyrimidine	1	92.1×	0.014	POT1
Inhibition of DNA recombination at telomere	1	84.0×	0.014	POT1
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.014	POT1
Meiotic synapsis	1	70.5×	0.015	POT1
MAPK6/MAPK4 signaling	1	68.0×	0.015	RAG1

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
positive regulation of DNA strand elongation	1	8426.0×	0.002	POT1
positive regulation of telomeric D-loop disassembly	1	8426.0×	0.002	POT1
pre-B cell allelic exclusion	1	2808.7×	0.003	RAG1
telomere assembly	1	2106.5×	0.003	POT1
regulation of behavioral fear response	1	2106.5×	0.003	RAG1
regulation of double-strand break repair via nonhomologous end joining	1	1685.2×	0.003	POT1
regulation of telomere maintenance via telomerase	1	1404.3×	0.003	POT1
V(D)J recombination	1	1053.2×	0.003	RAG1
establishment of protein localization to telomere	1	1053.2×	0.003	POT1
telomeric D-loop disassembly	1	936.2×	0.003	POT1
negative regulation of thymocyte apoptotic process	1	842.6×	0.003	RAG1
telomere capping	1	648.1×	0.003	POT1
telomere maintenance via telomerase	1	366.4×	0.005	POT1
negative regulation of telomere maintenance via telomerase	1	366.4×	0.005	POT1
positive regulation of telomere maintenance via telomerase	1	366.4×	0.005	POT1
positive regulation of telomere maintenance	1	255.3×	0.007	POT1
T cell homeostasis	1	227.7×	0.007	RAG1
positive regulation of T cell differentiation	1	227.7×	0.007	RAG1
T cell differentiation in thymus	1	205.5×	0.007	RAG1
DNA recombination	1	168.5×	0.008	RAG1
thymus development	1	168.5×	0.008	RAG1
visual learning	1	153.2×	0.008	RAG1
protein autoubiquitination	1	117.0×	0.010	RAG1
B cell differentiation	1	109.4×	0.010	RAG1
chromatin organization	1	49.6×	0.022	RAG1
adaptive immune response	1	42.1×	0.025	RAG1
immune response	1	23.5×	0.042	RAG1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

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
POT1	0	0
RAG1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
POT1	1	Binding:1

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

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	POT1, RAG1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
POT1	1	—
RAG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.