Nongerminomatous germ cell tumor

Summary

Nongerminomatous germ cell tumor (MONDO:0021656) is a cancer with 1 cohort gene (1 CIViC-evidence somatic driver; 1 ClinVar predisposition record) and 6 clinical trials. Top therapeutic interventions include etoposide phosphate and ifosfamide.

At a glance

• Classification: Cancer
• Cohort genes: 1
• ClinVar variants: 1
• Clinical trials: 6

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nongerminomatous germ cell tumor
Mondo ID	MONDO:0021656
NCIT	C121619
UMLS	C1266158
MedGen	220426
GARD	0010165
Is cancer (heuristic)	yes

Also known as: non-dysgerminomatous germ cell tumor · non-dysgerminomatous germ cell tumour · non-germinomatous germ cell tumor · non-germinomatous germ cell tumour · non-seminomatous germ cell tumor · non-seminomatous germ cell tumour · Nongerminomatous germ cell tumor · Nongerminomatous germ cell tumor Including central nervous system · Nongerminomatous germ cell tumour · Nongerminomatous germ cell tumour Including central nervous system · NSGCT

Data availability: 1 ClinVar variant.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › germ cell tumor › nongerminomatous germ cell tumor

Related subtypes (12): fallopian tube germ cell tumor, retroperitoneal germ cell neoplasm, childhood germ cell tumor, choriocarcinoma, malignant germ cell tumor, ovarian germ cell tumor, extragonadal germ cell tumor, gonadal germ cell tumor, germinomatous germ cell tumor, germ cell tumor of the vulva, adult germ cell tumor, germ cell benign neoplasm

Subtypes (3): teratoma, malignant non-dysgerminomatous germ cell tumor of ovary, extragonadal non-dysgerminomatous germ cell tumor

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

1 retrieved; paginated sample, class counts are floors:

1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
13961	NM_004333.6(BRAF):c.1799T>A (p.Val600Glu)	BRAF	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
BRAF	Act	BLCA,BRCA,CHOL,CLLSLL,COAD,COADREAD,CSCC,DLBCLNOS,GBM,GIST,HGGNOS,LGGNOS,LUAD,MEL,MLYM,NSCLC,OVT,PAST,PCM,PRAD,PRCC,PROSTATE,READ,SACA,SKCM,STAD,UCEC,WDTC	CIViC #5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	27.7×	0.036

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 39. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by MRAS-complex mutants	1	2855.0×	0.004	BRAF
Signalling to p38 via RIT and RIN	1	2284.0×	0.004	BRAF
Negative feedback regulation of MAPK pathway	1	1903.3×	0.004	BRAF
ARMS-mediated activation	1	1631.4×	0.004	BRAF
Prolonged ERK activation events	1	1427.5×	0.004	BRAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	1427.5×	0.004	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	1427.5×	0.004	BRAF
Signaling by FGFR3	1	1142.0×	0.004	BRAF
Signaling by FGFR4	1	1038.2×	0.004	BRAF
Frs2-mediated activation	1	951.7×	0.004	BRAF
Signaling by FGFR1	1	815.7×	0.004	BRAF
Spry regulation of FGF signaling	1	713.8×	0.005	BRAF
Signalling to ERKs	1	601.0×	0.005	BRAF
Negative regulation of FGFR3 signaling	1	439.2×	0.005	BRAF
Signaling by RAS mutants	1	423.0×	0.005	BRAF
Negative regulation of FGFR4 signaling	1	407.9×	0.005	BRAF
Signaling by FGFR2	1	407.9×	0.005	BRAF
Negative regulation of FGFR1 signaling	1	368.4×	0.005	BRAF
Negative regulation of FGFR2 signaling	1	368.4×	0.005	BRAF
Signaling by FGFR	1	346.1×	0.005	BRAF
RAF activation	1	335.9×	0.005	BRAF
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.005	BRAF
MAP2K and MAPK activation	1	285.5×	0.005	BRAF
Signaling by RAF1 mutants	1	278.5×	0.005	BRAF
Negative regulation of MAPK pathway	1	265.6×	0.005	BRAF
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.005	BRAF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.005	BRAF
Signaling downstream of RAS mutants	1	253.8×	0.005	BRAF
Oncogenic MAPK signaling	1	248.3×	0.005	BRAF
Signaling by NTRK1 (TRKA)	1	196.9×	0.007	BRAF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	5617.3×	0.003	BRAF
positive regulation of axon regeneration	1	3370.4×	0.003	BRAF
negative regulation of synaptic vesicle exocytosis	1	3370.4×	0.003	BRAF
CD4-positive, alpha-beta T cell differentiation	1	2808.7×	0.003	BRAF
myeloid progenitor cell differentiation	1	2407.4×	0.003	BRAF
positive regulation of D-glucose transmembrane transport	1	2106.5×	0.003	BRAF
head morphogenesis	1	2106.5×	0.003	BRAF
establishment of protein localization to membrane	1	1872.4×	0.003	BRAF
negative regulation of fibroblast migration	1	1532.0×	0.003	BRAF
endothelial cell apoptotic process	1	1296.3×	0.003	BRAF
regulation of T cell differentiation	1	1203.7×	0.003	BRAF
face development	1	802.5×	0.003	BRAF
synaptic vesicle exocytosis	1	766.0×	0.003	BRAF
positive regulation of peptidyl-serine phosphorylation	1	766.0×	0.003	BRAF
stress fiber assembly	1	766.0×	0.003	BRAF
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.004	BRAF
positive regulation of axonogenesis	1	581.1×	0.004	BRAF
thyroid gland development	1	543.6×	0.004	BRAF
negative regulation of endothelial cell apoptotic process	1	495.6×	0.004	BRAF
T cell differentiation in thymus	1	411.0×	0.005	BRAF
positive regulation of substrate adhesion-dependent cell spreading	1	374.5×	0.005	BRAF
substrate adhesion-dependent cell spreading	1	343.9×	0.005	BRAF
thymus development	1	337.0×	0.005	BRAF
ERK1 and ERK2 cascade	1	318.0×	0.005	BRAF
positive regulation of stress fiber assembly	1	312.1×	0.005	BRAF
visual learning	1	306.4×	0.005	BRAF
long-term synaptic potentiation	1	280.9×	0.005	BRAF
epidermal growth factor receptor signaling pathway	1	247.8×	0.006	BRAF
somatic stem cell population maintenance	1	247.8×	0.006	BRAF
cellular response to xenobiotic stimulus	1	240.7×	0.006	BRAF

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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
BRAF	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, 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
BRAF	1,442

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

30 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)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF
BAFETINIB	2	BRAF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRAF
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: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	4
PHASE3	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02375204	PHASE3	ACTIVE_NOT_RECRUITING	Standard-Dose Combination Chemotherapy or High-Dose Combination Chemotherapy and Stem Cell Transplant in Treating Patients with Relapsed or Refractory Germ Cell Tumors
NCT04804007	PHASE2	RECRUITING	Maintenance Oral Etoposide or Observation Following High-dose Chemo for GCT
NCT04876456	PHASE2	ACTIVE_NOT_RECRUITING	A Phase II Trial of Cabozantinib With Patients With Refractory GCTs
NCT02317393	PHASE2	COMPLETED	Contribution of the Imaging to the Expression of intégrines αvβ3 for the Characterization of Residual Masses of Non-seminoma Tumors at the End of Chemotherapy
NCT02499952	PHASE2	TERMINATED	Pembrolizumab in Subjects With Incurable Platinum-Refractory Germ Cell Tumors
NCT05705687	Not specified	RECRUITING	Validation of a Treatment Algorithm for Poor-Risk NSGCTnon Seminomatous Germ-cell Tumors

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ETOPOSIDE PHOSPHATE	4	1
IFOSFAMIDE	4	1