Melanoma, cutaneous malignant, susceptibility to, 5

Summary

Melanoma, cutaneous malignant, susceptibility to, 5 (MONDO:0013133) is a cancer with 2 cohort genes (1 CIViC-evidence somatic driver; 527 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Cohort genes: 2
• ClinVar variants: 527

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	melanoma, cutaneous malignant, susceptibility to, 5
Mondo ID	MONDO:0013133
OMIM	613099
UMLS	C2751295
MedGen	416516
GARD	0027844
Is cancer (heuristic)	yes

Also known as: CMM5 · melanoma, cutaneous malignant, 5 · melanoma, cutaneous malignant, susceptibility to, 5 · melanoma, cutaneous malignant, susceptibility to, type 5

Data availability: 527 ClinVar variants.

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, 5

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, 6, melanoma, cutaneous malignant, susceptibility to, 8, melanoma, cutaneous malignant, susceptibility to, 9, 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

527 retrieved; paginated sample, class counts are floors:

327 uncertain significance, 93 likely benign, 45 conflicting classifications of pathogenicity, 32 benign, 29 benign/likely benign, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1169773	NM_002386.4(MC1R):c.401T>C (p.Phe134Ser)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14307	NM_002386.4(MC1R):c.880G>C (p.Asp294His)	MC1R	Conflicting classifications of pathogenicity; risk factor	criteria provided, conflicting classifications
14309	NM_002386.4(MC1R):c.252C>A (p.Asp84Glu)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14310	NM_002386.4(MC1R):c.478C>T (p.Arg160Trp)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
14312	NM_002386.4(MC1R):c.451C>T (p.Arg151Cys)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2042101	NM_002386.4(MC1R):c.541G>A (p.Ala181Thr)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2079206	NM_002386.4(MC1R):c.602T>C (p.Val201Ala)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
225411	NM_002386.4(MC1R):c.359T>C (p.Ile120Thr)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239153	NM_002386.4(MC1R):c.425G>A (p.Arg142His)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239154	NM_002386.4(MC1R):c.464T>C (p.Ile155Thr)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
239159	NM_002386.4(MC1R):c.67C>T (p.Gln23Ter)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
265230	NM_002386.4(MC1R):c.456C>A (p.Tyr152Ter)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2731636	NM_002386.4(MC1R):c.426C>G (p.Arg142=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2758892	NM_002386.4(MC1R):c.181G>A (p.Ala61Thr)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2813060	NM_002386.4(MC1R):c.567G>T (p.Leu189=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2832137	NM_002386.4(MC1R):c.207G>C (p.Leu69=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2888585	NM_002386.4(MC1R):c.75G>T (p.Gly25=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321418	NM_002386.4(MC1R):c.101G>A (p.Arg34Gln)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321419	NM_002386.4(MC1R):c.169G>A (p.Ala57Thr)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321420	NM_002386.4(MC1R):c.189C>T (p.Ile63=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321422	NM_002386.4(MC1R):c.247T>C (p.Ser83Pro)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321426	NM_002386.4(MC1R):c.325C>T (p.Arg109Trp)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321430	NM_002386.4(MC1R):c.515G>T (p.Ser172Ile)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321432	NM_002386.4(MC1R):c.556G>A (p.Val186Met)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
321435	NM_002386.4(MC1R):c.637C>T (p.Arg213Trp)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3543987	NM_002386.4(MC1R):c.576C>T (p.Leu192=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3543989	NM_002386.4(MC1R):c.744C>T (p.Gly248=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3543991	NM_002386.4(MC1R):c.485G>A (p.Arg162Gln)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3713046	NM_002386.4(MC1R):c.616C>T (p.Leu206=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3871135	NM_002386.4(MC1R):c.736C>T (p.Leu246=)	MC1R	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

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

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
FANCA	Act	PRAD	CIViC #1810

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FANCA	Orphanet:84	Fanconi anemia
MC1R	Orphanet:618	Familial melanoma
MC1R	Orphanet:79432	Oculocutaneous albinism type 2

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
FANCA	HGNC:3582	ENSG00000187741	O15360	Fanconi anemia group A protein	clinvar
MC1R	HGNC:6929	ENSG00000258839	Q01726	Melanocyte-stimulating hormone receptor	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FANCA	Fanconi anemia group A protein	DNA repair protein that may operate in a postreplication repair or a cell cycle checkpoint function.
MC1R	Melanocyte-stimulating hormone receptor	G protein-coupled receptor that binds melanocyte-stimulating hormones (alpha, beta, and gamma-MSH) and adrenocorticotropic hormone/ACTH, which are peptide products of the POMC precursor protein.

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
GPCR	1	12.0×	0.164
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FANCA	Other/Unknown	no		FANCA, Fanconi_A_N, Fanconi_A_C
MC1R	GPCR	yes		GPCR_Rhodpsn, MSH_rcpt, Melcrt_ACTH_rcpt

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
left testis	2
right testis	1
ventricular zone	1
granulocyte	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FANCA	185	ubiquitous	marker	right testis, ventricular zone, left testis
MC1R	180	broad	yes	granulocyte, right uterine tube, left testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FANCA	3,036
MC1R	1,169

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FANCA	O15360	6
MC1R	Q01726	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. 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
Fanconi Anemia Pathway	1	139.3×	0.046	FANCA
Transcriptional and post-translational regulation of MITF-M expression and activity	1	89.2×	0.046	MC1R
PKR-mediated signaling	1	70.5×	0.046	FANCA
MITF-M-regulated melanocyte development	1	57.1×	0.046	MC1R
Class A/1 (Rhodopsin-like receptors)	1	37.1×	0.046	MC1R
Peptide ligand-binding receptors	1	37.1×	0.046	MC1R
G alpha (s) signalling events	1	36.6×	0.046	MC1R
GPCR ligand binding	1	32.1×	0.046	MC1R
GPCR downstream signalling	1	21.7×	0.059	MC1R
Signaling by GPCR	1	20.0×	0.059	MC1R
Developmental Biology	1	7.2×	0.146	MC1R
Signal Transduction	1	5.1×	0.187	MC1R

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
regulation of germ cell proliferation	1	4213.0×	0.005	FANCA
regulation of CD40 signaling pathway	1	2106.5×	0.005	FANCA
positive regulation of feeding behavior	1	1203.7×	0.005	MC1R
regulation of regulatory T cell differentiation	1	936.2×	0.005	FANCA
positive regulation of melanin biosynthetic process	1	702.2×	0.005	MC1R
melanin biosynthetic process	1	648.1×	0.005	MC1R
UV-damage excision repair	1	648.1×	0.005	MC1R
UV protection	1	601.9×	0.005	MC1R
positive regulation of cAMP/PKA signal transduction	1	526.6×	0.005	MC1R
female gonad development	1	401.2×	0.006	FANCA
pigmentation	1	351.1×	0.006	MC1R
male meiotic nuclear division	1	271.8×	0.007	FANCA
interstrand cross-link repair	1	216.1×	0.009	FANCA
sensory perception of pain	1	187.2×	0.009	MC1R
G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger	1	156.0×	0.010	MC1R
negative regulation of tumor necrosis factor production	1	125.8×	0.012	MC1R
regulation of inflammatory response	1	84.3×	0.017	FANCA
male gonad development	1	78.0×	0.017	FANCA
phospholipase C-activating G protein-coupled receptor signaling pathway	1	65.8×	0.019	MC1R
protein-containing complex assembly	1	56.9×	0.020	FANCA
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	56.5×	0.020	MC1R
DNA repair	1	31.9×	0.034	FANCA
intracellular signal transduction	1	19.1×	0.054	MC1R
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	MC1R

Therapeutics

Drug target analysis

Approved (phase 4): 1 · 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).

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
MC1R	BREMELANOTIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MC1R	6	4
FANCA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BREMELANOTIDE	4	MC1R
SETMELANOTIDE	4	MC1R
AFAMELANOTIDE	4	MC1R
INTERMEDINE	2	MC1R
PL-8177	2	MC1R
DERSIMELAGON PHOSPHATE	1	MC1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MC1R	319	Functional:164, Binding:155

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MC1R	319

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

6 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)
BREMELANOTIDE	4	MC1R
SETMELANOTIDE	4	MC1R
AFAMELANOTIDE	4	MC1R
INTERMEDINE	2	MC1R
PL-8177	2	MC1R
DERSIMELAGON PHOSPHATE	1	MC1R

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MC1R
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	FANCA

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)
FANCA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.