Melanoma, cutaneous malignant, susceptibility to, 9

Summary

Melanoma, cutaneous malignant, susceptibility to, 9 (MONDO:0014056) is a cancer with 2 cohort genes (2 CIViC-evidence somatic drivers; 88 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Cohort genes: 2
• ClinVar variants: 88

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	melanoma, cutaneous malignant, susceptibility to, 9
Mondo ID	MONDO:0014056
OMIM	615134
UMLS	C3554574
MedGen	767488
GARD	0027856
Is cancer (heuristic)	yes

Also known as: CMM9 · melanoma, cutaneous malignant, 9 · melanoma, cutaneous malignant, susceptibility to, 9 · melanoma, cutaneous malignant, susceptibility to, type 9

Data availability: 88 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 › melanoma, cutaneous malignant, susceptibility to, 9

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, tumor predisposition syndrome 3

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

88 retrieved; paginated sample, class counts are floors:

33 conflicting classifications of pathogenicity, 25 uncertain significance, 16 benign/likely benign, 7 benign, 6 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
410651	NM_198253.3(TERT):c.336dup (p.Glu113fs)	TERT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
242210	NM_198253.3(TERT):c.-57A>C	LOC110806263	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12730	NM_198253.3(TERT):c.1234C>T (p.His412Tyr)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1554664	NM_198253.3(TERT):c.2971-14C>T	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
212398	NM_198253.3(TERT):c.1317GGA[2] (p.Glu441del)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242221	NM_198253.3(TERT):c.2001C>T (p.Tyr667=)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242235	NM_198253.3(TERT):c.2991G>A (p.Val997=)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242237	NM_198253.3(TERT):c.3257G>A (p.Arg1086His)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
263104	NM_198253.3(TERT):c.1849C>T (p.Leu617=)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
268080	NM_198253.3(TERT):c.887A>C (p.His296Pro)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289326	NM_198253.3(TERT):c.150G>A (p.Leu50=)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
36947	NM_198253.3(TERT):c.508G>A (p.Val170Met)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
39111	NM_198253.3(TERT):c.2177C>T (p.Thr726Met)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
410674	NM_198253.3(TERT):c.1931C>T (p.Thr644Met)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
446374	NM_198253.3(TERT):c.2287-5G>A	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471857	NM_198253.3(TERT):c.2221G>A (p.Val741Met)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471870	NM_198253.3(TERT):c.2580C>T (p.Asp860=)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471874	NM_198253.3(TERT):c.2702G>A (p.Arg901Gln)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471875	NM_198253.3(TERT):c.2744G>A (p.Gly915Asp)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471902	NM_198253.3(TERT):c.779G>A (p.Gly260Asp)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
471904	NM_198253.3(TERT):c.838G>A (p.Glu280Lys)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539196	NM_198253.3(TERT):c.2005C>T (p.Arg669Trp)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539202	NM_198253.3(TERT):c.1393G>C (p.Val465Leu)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539205	NM_198253.3(TERT):c.1954G>A (p.Glu652Lys)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539214	NM_198253.3(TERT):c.863C>T (p.Ala288Val)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
539216	NM_198253.3(TERT):c.2573G>A (p.Arg858Gln)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
567770	NM_198253.3(TERT):c.2263G>A (p.Val755Ile)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
579067	NM_198253.3(TERT):c.2012G>A (p.Arg671Gln)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
639956	NM_198253.3(TERT):c.895G>A (p.Val299Met)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
645310	NM_198253.3(TERT):c.567C>A (p.His189Gln)	TERT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
TERT	Act	PRCC	CIViC #79
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
TERT	Limited	Autosomal dominant	melanoma, cutaneous malignant, susceptibility to, 9	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TERT	Orphanet:146	Differentiated thyroid carcinoma
TERT	Orphanet:1501	Adrenocortical carcinoma
TERT	Orphanet:1775	Dyskeratosis congenita
TERT	Orphanet:2032	Idiopathic pulmonary fibrosis
TERT	Orphanet:2495	Meningioma
TERT	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
TERT	Orphanet:457246	Clear cell sarcoma of kidney
TERT	Orphanet:618	Familial melanoma
TERT	Orphanet:88	Idiopathic aplastic anemia
POT1	Orphanet:251627	Oligodendroglioma
POT1	Orphanet:251630	Anaplastic oligodendroglioma
POT1	Orphanet:618	Familial melanoma
POT1	Orphanet:67038	B-cell chronic lymphocytic leukemia

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
TERT	HGNC:11730	ENSG00000164362	O14746	Telomerase reverse transcriptase	gencc,clinvar
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TERT	Telomerase reverse transcriptase	Telomerase is a ribonucleoprotein enzyme essential for the replication of chromosome termini in most eukaryotes.
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TERT	Other/Unknown	no		RT_dom, Telomerase_RT, Telomerase_RBD
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
olfactory bulb	1
stromal cell of endometrium	1
type B pancreatic cell	1
calcaneal tendon	1
germinal epithelium of ovary	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TERT	105	broad	yes	stromal cell of endometrium, type B pancreatic cell, olfactory bulb
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TERT	5,717
POT1	1,842

Intra-cohort edges

A	B	Sources
POT1	TERT	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TERT	O14746	23
POT1	Q9NUX5	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 26. 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 Extension By Telomerase	2	456.8×	1e-04	TERT, POT1
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	815.7×	0.012	TERT
Telomere C-strand synthesis initiation	1	407.9×	0.012	POT1
Processive synthesis on the C-strand of the telomere	1	380.7×	0.012	POT1
Telomere C-strand (Lagging Strand) Synthesis	1	380.7×	0.012	POT1
Removal of the Flap Intermediate from the C-strand	1	317.2×	0.012	POT1
Extension of Telomeres	1	300.5×	0.012	TERT
Polymerase switching on the C-strand of the telomere	1	211.5×	0.015	POT1
Telomere Maintenance	1	184.2×	0.016	TERT
Packaging Of Telomere Ends	1	109.8×	0.018	POT1
Chromosome Maintenance	1	105.7×	0.018	TERT
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.018	POT1
Cleavage of the damaged purine	1	102.0×	0.018	POT1
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	92.1×	0.018	POT1
Cleavage of the damaged pyrimidine	1	92.1×	0.018	POT1
MITF-M-dependent gene expression	1	90.6×	0.018	TERT
Inhibition of DNA recombination at telomere	1	84.0×	0.018	POT1
DNA Damage/Telomere Stress Induced Senescence	1	81.6×	0.018	POT1
Meiotic synapsis	1	70.5×	0.019	POT1
Formation of the beta-catenin:TCF transactivating complex	1	60.1×	0.020	TERT
TCF dependent signaling in response to WNT	1	58.9×	0.020	TERT
MITF-M-regulated melanocyte development	1	57.1×	0.020	TERT
Signaling by WNT	1	56.0×	0.020	TERT
Cell Cycle	1	18.0×	0.059	TERT
Developmental Biology	1	7.2×	0.139	TERT
Signal Transduction	1	5.1×	0.187	TERT

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 protein localization to telomere	2	2106.5×	8e-06	TERT, POT1
telomere maintenance via telomerase	2	732.7×	4e-05	TERT, POT1
RNA-templated transcription	1	8426.0×	6e-04	TERT
DNA strand elongation	1	8426.0×	6e-04	TERT
positive regulation of DNA strand elongation	1	8426.0×	6e-04	POT1
siRNA transcription	1	8426.0×	6e-04	TERT
positive regulation of transdifferentiation	1	8426.0×	6e-04	TERT
positive regulation of telomeric D-loop disassembly	1	8426.0×	6e-04	POT1
RNA-templated DNA biosynthetic process	1	4213.0×	1e-03	TERT
positive regulation of hair cycle	1	4213.0×	1e-03	TERT
telomere assembly	1	2106.5×	0.002	POT1
regulation of double-strand break repair via nonhomologous end joining	1	1685.2×	0.002	POT1
regulation of telomere maintenance via telomerase	1	1404.3×	0.002	POT1
positive regulation of protein localization to nucleolus	1	1404.3×	0.002	TERT
siRNA processing	1	936.2×	0.003	TERT
telomeric D-loop disassembly	1	936.2×	0.003	POT1
telomere maintenance via recombination	1	766.0×	0.003	TERT
telomere capping	1	648.1×	0.004	POT1
replicative senescence	1	495.6×	0.004	TERT
positive regulation of vascular associated smooth muscle cell migration	1	495.6×	0.004	TERT
DNA biosynthetic process	1	401.2×	0.005	TERT
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
response to cadmium ion	1	366.4×	0.005	TERT
negative regulation of cellular senescence	1	324.1×	0.005	TERT
positive regulation of stem cell proliferation	1	263.3×	0.006	TERT
positive regulation of telomere maintenance	1	255.3×	0.006	POT1
negative regulation of endothelial cell apoptotic process	1	247.8×	0.006	TERT
positive regulation of D-glucose import across plasma membrane	1	227.7×	0.006	TERT
positive regulation of vascular associated smooth muscle cell proliferation	1	216.1×	0.006	TERT

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
TERT	BERBERINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TERT	10	4
POT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TERT	391	Binding:389, Functional:2
POT1	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TERT	391

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

10 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)
BERBERINE	4	TERT
DOXORUBICIN	4	TERT
RESVERATROL	3	TERT
EPIGALOCATECHIN GALLATE	3	TERT
PERIFOSINE	3	TERT
ISOMETAMIDIUM	2	TERT
HOMIDIUM BROMIDE	2	TERT
ALLICIN	2	TERT
OLEIC ACID	2	TERT
ETHACRIDINE	2	TERT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TERT
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	1	POT1

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)
POT1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.