Melanoma, cutaneous malignant, susceptibility to, 8

Summary

Melanoma, cutaneous malignant, susceptibility to, 8 (MONDO:0013759) is a cancer caused by MITF (GenCC Strong), with 2 cohort genes (2 CIViC-evidence somatic drivers; 843 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MITF (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 843

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	melanoma, cutaneous malignant, susceptibility to, 8
Mondo ID	MONDO:0013759
OMIM	614456
Orphanet	293822
UMLS	C3152204
MedGen	463554
GARD	0027852
Is cancer (heuristic)	yes

Also known as: CMM8 · melanoma, cutaneous malignant, susceptibility to, 8 · melanoma, cutaneous malignant, susceptibility to, type 8 · MITF-related melanoma and renal cell carcinoma predisposition syndrome

Data availability: 843 ClinVar variants · 4 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, 8

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, 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

600 retrieved; paginated sample, class counts are floors:

328 uncertain significance, 201 likely benign, 31 conflicting classifications of pathogenicity, 18 pathogenic, 8 benign/likely benign, 6 likely pathogenic, 4 benign, 3 pathogenic/likely pathogenic, 1 pathogenic/likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1324720	NM_001354604.2(MITF):c.1061T>G (p.Leu354Ter)	MITF	Pathogenic	criteria provided, single submitter
14272	NM_001354604.2(MITF):c.964AGA[2] (p.Arg324del)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
2020473	NM_001354604.2(MITF):c.764T>A (p.Leu255Ter)	MITF	Pathogenic	criteria provided, single submitter
2024980	NM_001354604.2(MITF):c.643_644dup (p.Ser216fs)	MITF	Pathogenic	criteria provided, single submitter
2203401	NM_001354604.2(MITF):c.815del (p.Pro272fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
228363	NM_001354604.2(MITF):c.1129C>T (p.Arg377Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2422628	NC_000003.11:g.(?69985874)(70014399_?)del	MITF	Pathogenic	criteria provided, single submitter
2422629	NC_000003.11:g.(?70013978)(70014399_?)del	MITF	Pathogenic	criteria provided, single submitter
2422630	NC_000003.11:g.(?69985874)(69990502_?)del	MITF	Pathogenic	criteria provided, single submitter
2922420	NM_001354604.2(MITF):c.367del (p.Leu123fs)	MITF	Pathogenic	criteria provided, single submitter
2947585	NM_001354604.2(MITF):c.440T>G (p.Leu147Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29792	NM_001354604.2(MITF):c.1273G>A (p.Glu425Lys)	MITF	Pathogenic/Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
3601242	NM_001354604.2(MITF):c.673del (p.Asp225fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
3601257	NM_001354604.2(MITF):c.896_897del (p.Thr299fs)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
3601267	NM_001354604.2(MITF):c.970A>T (p.Arg324Ter)	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
372755	NM_001354604.2(MITF):c.1084C>T (p.Arg362Ter)	MITF	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3749427	NM_001354604.2(MITF):c.887_894dup (p.Thr299fs)	MITF	Pathogenic	criteria provided, single submitter
375217	NM_001354604.2(MITF):c.956-1G>A	MITF	Pathogenic	criteria provided, multiple submitters, no conflicts
3754752	NM_001354604.2(MITF):c.670del (p.Asp224fs)	MITF	Pathogenic	criteria provided, single submitter
3755219	NM_001354604.2(MITF):c.1177_1178del (p.Gln393fs)	MITF	Pathogenic	criteria provided, single submitter
3755317	NM_001354604.2(MITF):c.1185_1197dup (p.Arg400Ter)	MITF	Pathogenic	criteria provided, single submitter
3755923	NM_001354604.2(MITF):c.1179+2T>C	MITF	Pathogenic	criteria provided, single submitter
2034856	NM_001354604.2(MITF):c.953_955+3del	MITF	Likely pathogenic	criteria provided, single submitter
2422632	NC_000003.11:g.(?69987065)(69997137_?)del	MITF	Likely pathogenic	criteria provided, single submitter
2943395	NM_001354604.2(MITF):c.666+1G>A	MITF	Likely pathogenic	criteria provided, single submitter
2949158	NM_001354604.2(MITF):c.762+1G>A	MITF	Likely pathogenic	criteria provided, single submitter
2954027	NM_001354604.2(MITF):c.660_666+6del	MITF	Likely pathogenic	criteria provided, single submitter
3601255	NM_001354604.2(MITF):c.880+1G>A	MITF	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1186984	NM_001354604.2(MITF):c.1384G>A (p.Gly462Arg)	MITF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1196734	NM_001354604.2(MITF):c.956-3A>T	MITF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 12 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
MITF			CIViC #3527
TYR			CIViC #5972

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
MITF	Strong	Autosomal dominant	melanoma, cutaneous malignant, susceptibility to, 8	19

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MITF	Orphanet:293822	MITF-related melanoma and renal cell carcinoma predisposition syndrome
MITF	Orphanet:319298	Papillary renal cell carcinoma
MITF	Orphanet:404511	Clear cell papillary renal cell carcinoma
MITF	Orphanet:42665	Tietz syndrome
MITF	Orphanet:618	Familial melanoma
MITF	Orphanet:895	Waardenburg syndrome type 2
MITF	Orphanet:897	Waardenburg-Shah syndrome
TYR	Orphanet:352734	Minimal pigment oculocutaneous albinism type 1
TYR	Orphanet:352737	Temperature-sensitive oculocutaneous albinism type 1
TYR	Orphanet:79431	Oculocutaneous albinism type 1A
TYR	Orphanet:79434	Oculocutaneous albinism type 1B
TYR	Orphanet:895	Waardenburg syndrome 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
MITF	HGNC:7105	ENSG00000187098	O75030	Microphthalmia-associated transcription factor	gencc,clinvar
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MITF	Microphthalmia-associated transcription factor	Transcription factor that acts as a master regulator of melanocyte survival and differentiation as well as melanosome biogenesis.
TYR	Tyrosinase	This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MITF	Transcription factor	no		bHLH_dom, MiT/TFE_C, MiT/TFE_N
TYR	Enzyme (other)	yes	1.14.18.1	Tyrosinase_Cu-bd, Di-copper_centre_dom_sf, Tyrosinase/Hemocyanin

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
pigmented layer of retina	2
retina	1
skeletal muscle tissue of biceps brachii	1
male germ line stem cell (sensu Vertebrata) in testis	1
upper leg skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MITF	293	ubiquitous	marker	pigmented layer of retina, retina, skeletal muscle tissue of biceps brachii
TYR	59	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, upper leg skin

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TYR	3,663
MITF	2,908

Intra-cohort edges

A	B	Sources
MITF	TYR	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MITF	O75030	12
TYR	P14679	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. 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
Regulation of MITF-M-dependent genes involved in pigmentation	2	265.6×	2e-04	MITF, TYR
Regulation of MITF-M dependent genes involved in metabolism	1	1903.3×	0.004	MITF
Regulation of MITF-M dependent genes involved in invasion	1	1427.5×	0.004	MITF
Melanin biosynthesis	1	1142.0×	0.004	TYR
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	815.7×	0.004	MITF
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	439.2×	0.006	MITF
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	1	335.9×	0.006	MITF
Regulation of MITF-M-dependent genes involved in apoptosis	1	317.2×	0.006	MITF
SUMOylation of transcription factors	1	285.5×	0.006	MITF
Regulation of MITF-M-dependent genes involved in cell cycle and proliferation	1	285.5×	0.006	MITF
SUMO E3 ligases SUMOylate target proteins	1	89.2×	0.016	MITF
Transcriptional and post-translational regulation of MITF-M expression and activity	1	89.2×	0.016	MITF
SUMOylation	1	81.6×	0.016	MITF
MITF-M-regulated melanocyte development	1	57.1×	0.021	MITF
Post-translational protein modification	1	9.6×	0.115	MITF
Developmental Biology	1	7.2×	0.142	MITF
Metabolism of proteins	1	6.2×	0.155	MITF

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
eye pigment biosynthetic process	1	4213.0×	0.002	TYR
melanocyte apoptotic process	1	4213.0×	0.002	MITF
regulation of RNA biosynthetic process	1	4213.0×	0.002	MITF
melanin biosynthetic process from tyrosine	1	2106.5×	0.004	TYR
response to blue light	1	1685.2×	0.004	TYR
positive regulation of DNA-templated transcription initiation	1	936.2×	0.006	MITF
regulation of osteoclast differentiation	1	766.0×	0.006	MITF
melanin biosynthetic process	1	648.1×	0.006	TYR
bone remodeling	1	468.1×	0.007	MITF
melanocyte differentiation	1	401.2×	0.007	MITF
response to vitamin D	1	401.2×	0.007	TYR
pigmentation	1	351.1×	0.007	TYR
response to cAMP	1	255.3×	0.009	TYR
response to UV	1	183.2×	0.011	TYR
camera-type eye development	1	179.3×	0.011	MITF
osteoclast differentiation	1	172.0×	0.011	MITF
thymus development	1	168.5×	0.011	TYR
cell fate commitment	1	147.8×	0.012	MITF
regulation of cell population proliferation	1	57.7×	0.026	MITF
protein-containing complex assembly	1	56.9×	0.026	MITF
negative regulation of cell migration	1	55.8×	0.026	MITF
cell population proliferation	1	51.4×	0.027	TYR
Wnt signaling pathway	1	49.9×	0.027	MITF
visual perception	1	39.8×	0.032	TYR
positive regulation of gene expression	1	19.4×	0.063	MITF
negative regulation of apoptotic process	1	17.4×	0.068	MITF
regulation of DNA-templated transcription	1	15.8×	0.072	MITF
positive regulation of DNA-templated transcription	1	14.0×	0.078	MITF
negative regulation of transcription by RNA polymerase II	1	8.9×	0.117	MITF
positive regulation of transcription by RNA polymerase II	1	7.4×	0.134	MITF

Therapeutics

Drug target analysis

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

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
MITF	PERHEXILINE MALEATE
TYR	ASCORBIC ACID

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TYR	10	4
MITF	3	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PERHEXILINE MALEATE	4	MITF
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
NIFUROXAZIDE	3	MITF
CURCUMIN	3	TYR
RESVERATROL	3	TYR
QUERCETIN	3	TYR
HOMIDIUM BROMIDE	2	MITF
BUTYLATED HYDROXYTOLUENE	2	TYR
LUTEOLIN	2	TYR
ARBUTIN	2	TYR
KAEMPFEROL	1	TYR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TYR	211	Binding:209, ADMET:2
MITF	10	Functional:10

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TYR	1.14.18.1	tyrosinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TYR	211

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

13 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)
PERHEXILINE MALEATE	4	MITF
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
NIFUROXAZIDE	3	MITF
CURCUMIN	3	TYR
RESVERATROL	3	TYR
QUERCETIN	3	TYR
HOMIDIUM BROMIDE	2	MITF
BUTYLATED HYDROXYTOLUENE	2	TYR
LUTEOLIN	2	TYR
ARBUTIN	2	TYR
KAEMPFEROL	1	TYR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	MITF, TYR
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.