diffuse midline glioma, H3 K27-altered

disease

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Also known as DMG, H3 K27-altered

Summary

diffuse midline glioma, H3 K27-altered (MONDO:1060171) is a cancer with 29 cohort genes (24 CIViC-evidence somatic drivers; 44 ClinVar predisposition records) and 3 clinical trials. The dominant Reactome pathway is Impaired BRCA2 binding to PALB2 (5 cohort genes). Molecularly, H3-3A K28M confers sensitivity to Dordaviprone in Diffuse Midline Glioma, H3 K27-altered (CIViC Level A); 5 further subtype–drug associations are mapped below. Top therapeutic interventions include lutetium lu-177 vipivotide tetraxetan.

At a glance

Classification: Cancer
Cohort genes: 29
ClinVar variants: 44
Clinical trials: 3
Precision-medicine evidence (CIViC): 6 subtype–drug associations

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	diffuse midline glioma, H3 K27-altered
Mondo ID	MONDO:1060171
NCIT	C185368
UMLS	C5669877
MedGen	1811313
GARD	0028173
Is cancer (heuristic)	yes

Also known as: DMG, H3 K27-altered

Data availability: 44 ClinVar variants.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: neoplasm › cancer › nervous system cancer › central nervous system cancer › brain cancer › infratentorial cancer › brainstem cancer › brain stem glioma › childhood brain stem glioma › diffuse intrinsic pontine glioma › diffuse midline glioma, H3 K27-altered

Subtypes (1): diffuse midline glioma, H3 K27M-mutant

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

44 retrieved; paginated sample, class counts are floors:

24 uncertain significance, 12 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 2 likely pathogenic, 1 benign, 1 pathogenic, 1 conflicting classifications of pathogenicity; association; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
52536	NM_000059.4(BRCA2):c.8247_8248del (p.Lys2750fs)	BRCA2	Pathogenic	reviewed by expert panel
140877	NM_001048174.2(MUTYH):c.650G>A (p.Arg217His)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5294	NM_001048174.2(MUTYH):c.1103G>A (p.Gly368Asp)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
127893	NM_002878.4(RAD51D):c.694C>T (p.Arg232Ter)	RAD51D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2572091	NM_004360.5(CDH1):c.1679_1680insT (p.Tyr561fs)	CDH1	Likely pathogenic	criteria provided, single submitter
8742	NM_004168.4(SDHA):c.1660C>T (p.Arg554Trp)	SDHA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
470770	NM_004304.5(ALK):c.1720G>A (p.Gly574Arg)	ALK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
127306	NM_000038.6(APC):c.5528C>T (p.Pro1843Leu)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
142201	NM_000038.6(APC):c.4765C>G (p.Arg1589Gly)	APC	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
822	NM_000038.6(APC):c.3920T>A (p.Ile1307Lys)	APC	Conflicting classifications of pathogenicity; association; risk factor	criteria provided, conflicting classifications
141389	NM_000051.4(ATM):c.4673C>T (p.Thr1558Met)	ATM	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
134026	NM_005228.5(EGFR):c.2224G>A (p.Val742Ile)	EGFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
584703	NM_005228.5(EGFR):c.3629C>T (p.Ala1210Val)	EGFR	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
101036	NM_006767.4(LZTR1):c.2062C>T (p.Arg688Cys)	LZTR1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
6946	NM_002485.5(NBN):c.511A>G (p.Ile171Val)	NBN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
322569	NM_001042492.3(NF1):c.1444A>G (p.Thr482Ala)	NF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
141109	NM_024675.4(PALB2):c.2743G>A (p.Ala915Thr)	PALB2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
540824	NM_006231.4(POLE):c.4231A>G (p.Ile1411Val)	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
475020	NM_015450.3(POT1):c.1127A>G (p.Gln376Arg)	POT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
140912	NM_000051.4(ATM):c.1624T>G (p.Leu542Val)	ATM	Uncertain significance	criteria provided, multiple submitters, no conflicts
142096	NM_000051.4(ATM):c.692A>G (p.His231Arg)	ATM	Uncertain significance	criteria provided, multiple submitters, no conflicts
2805839	NM_004333.6(BRAF):c.205G>A (p.Gly69Ser)	BRAF	Uncertain significance	criteria provided, multiple submitters, no conflicts
2572663	NM_032977.4(CASP10):c.11A>G (p.Gln4Arg)	CASP10	Uncertain significance	criteria provided, multiple submitters, no conflicts
1692949	NM_007194.4(CHEK2):c.521T>C (p.Leu174Pro)	CHEK2	Uncertain significance	criteria provided, multiple submitters, no conflicts
2572374	NM_005228.5(EGFR):c.3247G>C (p.Asp1083His)	EGFR	Uncertain significance	criteria provided, single submitter
841628	NM_005228.5(EGFR):c.3086C>T (p.Thr1029Met)	EGFR	Uncertain significance	criteria provided, multiple submitters, no conflicts
2573111	NM_005896.4(IDH1):c.676A>G (p.Ile226Val)	IDH1	Uncertain significance	criteria provided, single submitter
943065	NM_006231.4(POLE):c.13A>G (p.Ser5Gly)	LOC130009266	Uncertain significance	criteria provided, multiple submitters, no conflicts
1206269	NM_006767.4(LZTR1):c.1615+5G>A	LZTR1	Uncertain significance	criteria provided, multiple submitters, no conflicts
548121	NM_006767.4(LZTR1):c.2093C>T (p.Ser698Phe)	LZTR1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 131 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
ACVR1	Act	HGGNOS,HNSC,UCEC	CIViC #154
H3-3A	Act	HGGNOS,PAST	CIViC #2537
H3C2	Act	BLCA,BRCA,DLBCLNOS,ESCA	CIViC #6614
SDHA	Act	CHRCC,HCC,LGGNOS	CIViC #5176
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
BRCA2	LoF	BLCA,BRCA,CESC,CHOL,HCC,HNSC,LUSC,MBL,OVT,PAAD,PRAD,PROSTATE,RCC,VULVA	CIViC #7
SMARCA4	Act	BL,BLADDER,BLCA,CCRCC,CHOL,COAD,COADREAD,EGC,ESCA,ESCC,HCC,HNSC,LGGNOS,LUAD,MBL,MLYM,NHL,NSCLC,OVT,PAAD,PANCREAS,PAST,PRCC,SACA,STAD,THYM	CIViC #78
VHL	LoF	CCRCC,PGNG,RCC	CIViC #58
CHEK2	Act	BRCA	CIViC #8950
DICER1	LoF	COADREAD,CSCC,MEL,UCEC	CIViC #9533
POT1	Act	ANGS,CLLSLL,LGGNOS,MEL,SOFT_TISSUE	CIViC #9935
CDH1	LoF	BLCA,BRCA,CSCC,DLBCLNOS,ESCA,STAD	CIViC #888
PALB2	LoF	OVT	CIViC #15013
EGFR	Act	BRCA,COADREAD,GB,GBM,HGGNOS,LGGNOS,LUAD,LUSC,NSCLC,PAST,PCM,READ,SIC	CIViC #19
ALK	Act	BRCA,HCC,NBL,NSCLC,PROSTATE,SCLC	CIViC #1
IDH1	Act	AML,CHOL,GB,GBM,HCC,HGGNOS,LGGNOS,MBL,MEL,MT,OS,PAST,PCM,PRAD,SKCM	CIViC #26
APC	LoF	AML,ANSC,CHOL,COAD,COADREAD,CSCC,EGC,ESCA,ESCC,HCC,LUAD,MEL,MT,NETNOS,NSCLC,PRAD,PROSTATE,READ,STAD,STOMACH,UM,VULVA	CIViC #66
LZTR1	LoF	GBM,HCC,PRAD,UCEC	CIViC #6523
MEN1	LoF	ACC,BLCA,BRCA,HCC,LUNG,PANCREAS,PANET,WDTC	CIViC #3485
MSH3			CIViC #3629
NF1	LoF	ACC,ALL,AML,ANGS,BLCA,BRCA,CCRCC,CHOL,CLLSLL,COADREAD,GB,GBM,GIST,HCC,HNSC,LGGNOS,LMS,LUAD,LUNG,LUSC,MEL,NBL,NSCLC,OVT,PAST,PGNG,PLMESO,RMS,SKCM,SOFT_TISSUE,STAD,THYM,UCS	CIViC #3867
ATM	LoF	BLCA,BRCA,CCRCC,CHOL,CLLSLL,COAD,COADREAD,ESCA,HCC,LUAD,LUSC,MEL,NSCLC,PAAD,PANCREAS,PANET,PCM,PLMESO,PRAD,PROSTATE,STAD,UCEC,UTUC,WDTC	CIViC #69
POLE	Act	ACC,BLCA	CIViC #4386
RAD51D			CIViC #4765

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACVR1	Orphanet:337	Fibrodysplasia ossificans progressiva
SDHA	Orphanet:139411	Carney triad
SDHA	Orphanet:154	Familial isolated dilated cardiomyopathy
SDHA	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
SDHA	Orphanet:3208	Isolated succinate-CoQ reductase deficiency
SDHA	Orphanet:44890	Gastrointestinal stromal tumor
SDHA	Orphanet:97286	Carney-Stratakis syndrome
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
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
SMARCA4	Orphanet:1465	Coffin-Siris syndrome
SMARCA4	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCA4	Orphanet:370396	Small cell carcinoma of the ovary
SMARCA4	Orphanet:466962	SMARCA4-deficient sarcoma of thorax
VHL	Orphanet:238557	Chuvash erythrocytosis
VHL	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
VHL	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
VHL	Orphanet:892	Von Hippel-Lindau disease
SAMD9	Orphanet:306658	Familial normophosphatemic tumoral calcinosis
SAMD9	Orphanet:494433	MIRAGE syndrome
CASP10	Orphanet:3261	Autoimmune lymphoproliferative syndrome
CHEK2	Orphanet:1331	Familial prostate cancer
CHEK2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
CHEK2	Orphanet:440437	Familial colorectal cancer Type X
CHEK2	Orphanet:524	Li-Fraumeni syndrome
CHEK2	Orphanet:668	Osteosarcoma
DICER1	Orphanet:276399	Familial multinodular goiter
DICER1	Orphanet:284343	DICER1 tumor-predisposition syndrome
DICER1	Orphanet:404476	Global developmental delay-lung cysts-overgrowth-Wilms tumor syndrome
DICER1	Orphanet:99757	Embryonal rhabdomyosarcoma

Cohort genes → proteins

29 cohort genes, 29 distinct canonical proteins.

Evidence partition

Subset	Genes
civic_only	3
multi_evidence	26

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACVR1	HGNC:171	ENSG00000115170	Q04771	Activin receptor type-1	civic_evidence
H3-3A	HGNC:4764	ENSG00000163041	P84243	Histone H3.3	civic_evidence
H3C2	HGNC:4776	ENSG00000286522	P68431	Histone H3.1	civic_evidence
SDHA	HGNC:10680	ENSG00000073578	P31040	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	clinvar
VHL	HGNC:12687	ENSG00000134086	P40337	von Hippel-Lindau disease tumor suppressor	clinvar
SAMD9	HGNC:1348	ENSG00000205413	Q5K651	Sterile alpha motif domain-containing protein 9	clinvar
CASP10	HGNC:1500	ENSG00000003400	Q92851	Caspase-10	clinvar
CHEK2	HGNC:16627	ENSG00000183765	O96017	Serine/threonine-protein kinase Chk2	clinvar
DICER1	HGNC:17098	ENSG00000100697	Q9UPY3	Endoribonuclease Dicer	clinvar
POT1	HGNC:17284	ENSG00000128513	Q9NUX5	Protection of telomeres protein 1	clinvar
CDH1	HGNC:1748	ENSG00000039068	P12830	Cadherin-1	clinvar
PALB2	HGNC:26144	ENSG00000083093	Q86YC2	Partner and localizer of BRCA2	clinvar
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	clinvar
ALK	HGNC:427	ENSG00000171094	Q9UM73	ALK tyrosine kinase receptor	clinvar
IDH1	HGNC:5382	ENSG00000138413	O75874	Isocitrate dehydrogenase [NADP] cytoplasmic	clinvar
APC	HGNC:583	ENSG00000134982	P25054	Adenomatous polyposis coli protein	clinvar
LZTR1	HGNC:6742	ENSG00000099949	Q8N653	Leucine-zipper-like transcriptional regulator 1	clinvar
MEN1	HGNC:7010	ENSG00000133895	O00255	Menin	clinvar
MSH3	HGNC:7326	ENSG00000113318	P20585	DNA mismatch repair protein Msh3	clinvar
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar
NBN	HGNC:7652	ENSG00000104320	O60934	Nibrin	clinvar
NF1	HGNC:7765	ENSG00000196712	P21359	Neurofibromin	clinvar
ATM	HGNC:795	ENSG00000149311	Q13315	Serine-protein kinase ATM	clinvar
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	clinvar
PTCH2	HGNC:9586	ENSG00000117425	Q9Y6C5	Protein patched homolog 2	clinvar
RAD51D	HGNC:9823	ENSG00000185379	O75771	DNA repair protein RAD51 homolog 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACVR1	Activin receptor type-1	Bone morphogenetic protein (BMP) type I receptor that is involved in a wide variety of biological processes, including bone, heart, cartilage, nervous, and reproductive system development and regulation.
H3-3A	Histone H3.3	Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes.
H3C2	Histone H3.1	Core component of nucleosome.
SDHA	Succinate dehydrogenase [ubiquinone] flavoprotein subunit, mitochondrial	Flavoprotein (FP) subunit of succinate dehydrogenase (SDH) that is involved in complex II of the mitochondrial electron transport chain and is responsible for transferring electrons from succinate to ubiquinone (coenzyme Q).
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
VHL	von Hippel-Lindau disease tumor suppressor	Involved in the ubiquitination and subsequent proteasomal degradation via the von Hippel-Lindau ubiquitination complex.
SAMD9	Sterile alpha motif domain-containing protein 9	Double-stranded nucleic acid binding that acts as an antiviral factor by playing an essential role in the formation of cytoplasmic antiviral granules.
CASP10	Caspase-10	Involved in the activation cascade of caspases responsible for apoptosis execution.
CHEK2	Serine/threonine-protein kinase Chk2	Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest, activation of DNA repair and apoptosis in response to the presence of DNA double-strand breaks.
DICER1	Endoribonuclease Dicer	Double-stranded RNA (dsRNA) endoribonuclease playing a central role in short dsRNA-mediated post-transcriptional gene silencing.
POT1	Protection of telomeres protein 1	Component of the telomerase ribonucleoprotein (RNP) complex that is essential for the replication of chromosome termini.
CDH1	Cadherin-1	Cadherins are calcium-dependent cell adhesion proteins.
PALB2	Partner and localizer of BRCA2	Plays a critical role in homologous recombination repair (HRR) through its ability to recruit BRCA2 and RAD51 to DNA breaks.
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
ALK	ALK tyrosine kinase receptor	Neuronal receptor tyrosine kinase that is essentially and transiently expressed in specific regions of the central and peripheral nervous systems and plays an important role in the genesis and differentiation of the nervous system.
IDH1	Isocitrate dehydrogenase [NADP] cytoplasmic	Catalyzes the NADP(+)-dependent oxidative decarboxylation of isocitrate (D-threo-isocitrate) to 2-ketoglutarate (2-oxoglutarate), which is required by other enzymes such as the phytanoyl-CoA dioxygenase.
APC	Adenomatous polyposis coli protein	Tumor suppressor.
LZTR1	Leucine-zipper-like transcriptional regulator 1	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex that mediates ubiquitination of Ras (K-Ras/KRAS, N-Ras/NRAS and H-Ras/HRAS).
MEN1	Menin	Essential component of a MLL/SET1 histone methyltransferase (HMT) complex, a complex that specifically methylates ‘Lys-4’ of histone H3 (H3K4).
MSH3	DNA mismatch repair protein Msh3	Component of the post-replicative DNA mismatch repair system (MMR).
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.
NBN	Nibrin	Component of the MRN complex, which plays a central role in double-strand break (DSB) repair, DNA recombination, maintenance of telomere integrity and meiosis.
NF1	Neurofibromin	Stimulates the GTPase activity of Ras.
ATM	Serine-protein kinase ATM	Serine/threonine protein kinase which activates checkpoint signaling upon double strand breaks (DSBs), apoptosis and genotoxic stresses such as ionizing ultraviolet A light (UVA), thereby acting as a DNA damage sensor.
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.
PTCH2	Protein patched homolog 2	Plays a role in the control of cellular growth.
RAD51D	DNA repair protein RAD51 homolog 4	Involved in the homologous recombination repair (HRR) pathway of double-stranded DNA breaks arising during DNA replication or induced by DNA-damaging agents.

Protein-family classification

Druggable: 10 · Difficult: 2 · Unknown: 17 · Druggable fraction: 0.34

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	6	5.7×	0.003
Enzyme (other)	4	1.6×	0.549
Other/Unknown	17	1.1×	0.761
Scaffold/PPI	1	0.6×	0.976
Transcription factor	1	0.3×	0.976

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACVR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
H3-3A	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, Histone-fold
H3C2	Other/Unknown	no		Histone_H3/CENP-A, H2A/H2B/H3, Histone-fold
SDHA	Other/Unknown	no		FRD_SDH_FAD_BS, FAD-dep_OxRdtase_2_FAD-bd, Succ_DH_flav_su_fwd
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
VHL	Enzyme (other)	yes	2.3.2.B13	VHL_tumour_suppress_b/a_dom, VHL_alpha_dom, VHL_beta_dom
SAMD9	Other/Unknown	no		SAM, SAM/pointed_sf, P-loop_NTPase
CASP10	Enzyme (other)	yes	3.4.22.63	Pept_C14_p20, DED_dom, Pept_C14_p10
CHEK2	Kinase	yes	2.7.11.1	FHA_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
DICER1	Enzyme (other)	yes	3.1.26.3	RNase_III_dom, Helicase_C-like, PAZ_dom
POT1	Other/Unknown	no		Telomer_end-bd_POT1/Cdc13, NA-bd_OB-fold, POT1
CDH1	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin_pro_dom
PALB2	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, PALB2_WD40, WD40_repeat_dom_sf
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ALK	Kinase	yes	2.7.10.1	Prot_kinase_dom, MAM_dom, Ser-Thr/Tyr_kinase_cat_dom
IDH1	Enzyme (other)	yes	1.1.1.42	Isocitrate_DH_NADP, IsoCit/isopropylmalate_DH_CS, IsoPropMal-DH-like_dom
APC	Other/Unknown	no		Armadillo, APC_rpt, SAMP
LZTR1	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
MEN1	Other/Unknown	no		Menin
MSH3	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain
NBN	Other/Unknown	no		FHA_dom, BRCT_dom, SMAD_FHA_dom_sf
NF1	Other/Unknown	no		CRAL-TRIO_dom, RasGAP_dom, Rho_GTPase_activation_prot
ATM	Kinase	yes	2.7.11.1	PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
POLE	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B, RNaseH-like_sf
PTCH2	Other/Unknown	no		SSD, TM_rcpt_patched, HMGCR/SNAP/NPC1-like_SSD
RAD51D	Other/Unknown	no		AAA+_ATPase, Rad51_C, DNA_recomb/repair_RecA-like

Expression context

Cohort genes with no expression data: 0.

27 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)	29
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic epithelium	5
calcaneal tendon	4
male germ line stem cell (sensu Vertebrata) in testis	4
monocyte	3
adrenal tissue	3
buccal mucosa cell	3
secondary oocyte	3
right hemisphere of cerebellum	3
ganglionic eminence	2
ventricular zone	2
cortical plate	2
esophagus squamous epithelium	2
granulocyte	2
lower esophagus mucosa	2
cauda epididymis	2
gingival epithelium	2
jejunal mucosa	2
oocyte	2
male germ cell	2
sperm	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACVR1	293	ubiquitous	marker	cartilage tissue, synovial joint, saphenous vein
H3-3A	134	ubiquitous	marker	ganglionic eminence, monocyte, ventricular zone
H3C2	94	ubiquitous	marker	adrenal tissue, colonic epithelium, bone marrow cell
SDHA	143	ubiquitous	marker	apex of heart, heart left ventricle, mucosa of transverse colon
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
VHL	186	ubiquitous	marker	cortical plate, monocyte, mononuclear cell
SAMD9	247	ubiquitous	marker	esophagus squamous epithelium, amniotic fluid, epithelium of esophagus
CASP10	206	ubiquitous	marker	colonic epithelium, granulocyte, monocyte
CHEK2	183	ubiquitous	marker	primordial germ cell in gonad, lower esophagus mucosa, male germ line stem cell (sensu Vertebrata) in testis
DICER1	295	ubiquitous	marker	cauda epididymis, caput epididymis, tongue squamous epithelium
POT1	279	ubiquitous	marker	secondary oocyte, germinal epithelium of ovary, calcaneal tendon
CDH1	245	broad	marker	jejunal mucosa, esophagus squamous epithelium, gingival epithelium
PALB2	232	ubiquitous	yes	secondary oocyte, buccal mucosa cell, oocyte
EGFR	285	ubiquitous	marker	nipple, gingiva, gingival epithelium
ALK	181	broad	marker	sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis
IDH1	294	ubiquitous	marker	corpus epididymis, jejunal mucosa, adrenal tissue
APC	297	ubiquitous	marker	substantia nigra pars compacta, substantia nigra pars reticulata, medial globus pallidus
LZTR1	134	ubiquitous	marker	sural nerve, pituitary gland, adenohypophysis
MEN1	271	ubiquitous	marker	granulocyte, lower esophagus mucosa, right hemisphere of cerebellum
MSH3	287	ubiquitous	marker	buccal mucosa cell, bronchial epithelial cell, mucosa of paranasal sinus
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
NBN	299	ubiquitous	marker	endometrium epithelium, mammary duct, cauda epididymis
NF1	283	ubiquitous	marker	colonic epithelium, calcaneal tendon, adrenal tissue
ATM	286	ubiquitous	marker	calcaneal tendon, colonic epithelium, corpus callosum
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere
PTCH2	162	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right ovary
RAD51D	187	ubiquitous	yes	sperm, male germ cell, oocyte

Protein interactions among cohort

Intra-cohort edges: 23.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGFR	18,421
CDH1	8,738
DICER1	8,268
SMARCA4	8,138
BRAF	7,394
ATM	7,383
SDHA	6,141
PALB2	5,641
NF1	5,540
IDH1	5,464

Intra-cohort edges

A	B	Sources
ATM	BRCA2	string_interaction
ATM	CHEK2	string_interaction
ATM	NBN	biogrid_interaction, string_interaction
ATM	RAD51D	string_interaction
BRAF	BRCA2	biogrid_interaction
BRAF	EGFR	biogrid_interaction
BRAF	MEN1	intact
BRAF	NF1	string_interaction
BRAF	POLE	intact
BRAF	VHL	biogrid_interaction
BRCA2	CHEK2	string_interaction
BRCA2	NBN	string_interaction
BRCA2	PALB2	biogrid_interaction, intact, string_interaction
BRCA2	RAD51D	string_interaction
CDH1	EGFR	intact, string_interaction
CHEK2	NBN	string_interaction
CHEK2	PALB2	string_interaction
CHEK2	RAD51D	string_interaction
MSH3	MUTYH	string_interaction
MSH3	POLE	string_interaction
MUTYH	POLE	string_interaction
MUTYH	SMARCA4	intact
PALB2	RAD51D	string_interaction

Structural data

PDB: 27 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
H3C2	P68431	548
EGFR	P00533	388
VHL	P40337	142
BRAF	P15056	131
H3-3A	P84243	103
ACVR1	Q04771	85
ALK	Q9UM73	79
MEN1	O00255	69
IDH1	O75874	61
CHEK2	O96017	38
SMARCA4	P51532	31
APC	P25054	31
NF1	P21359	26
MSH3	P20585	24
CDH1	P12830	22
DICER1	Q9UPY3	21
POLE	Q07864	18
RAD51D	O75771	17
BRCA2	P51587	14
POT1	Q9NUX5	14
ATM	Q13315	14
SAMD9	Q5K651	7
NBN	O60934	7
SDHA	P31040	5
PALB2	Q86YC2	4
LZTR1	Q8N653	3
MUTYH	Q9UIF7	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PTCH2	Q9Y6C5	79.25
CASP10	Q92851	69.54

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 351. Enrichment computed across 29 evidence-associated genes (26 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 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Impaired BRCA2 binding to PALB2	5	87.8×	2e-07	BRCA2, PALB2, NBN, ATM, RAD51D
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	5	81.3×	2e-07	BRCA2, PALB2, NBN, ATM, RAD51D
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	5	81.3×	2e-07	BRCA2, PALB2, NBN, ATM, RAD51D
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	5	81.3×	2e-07	BRCA2, PALB2, NBN, ATM, RAD51D
HDR through Homologous Recombination (HRR)	6	43.9×	2e-07	BRCA2, PALB2, NBN, ATM, POLE, RAD51D
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	5	75.7×	3e-07	BRCA2, PALB2, NBN, ATM, RAD51D
Homologous DNA Pairing and Strand Exchange	5	73.2×	3e-07	BRCA2, PALB2, NBN, ATM, RAD51D
Resolution of D-loop Structures through Holliday Junction Intermediates	5	57.8×	9e-07	BRCA2, PALB2, NBN, ATM, RAD51D
Diseases of DNA repair	4	87.8×	4e-06	BRCA2, MSH3, NBN, ATM
Meiotic recombination	5	25.0×	5e-05	BRCA2, H3-3A, H3C2, NBN, ATM
Defective homologous recombination repair (HRR) due to PALB2 loss of function	3	109.8×	7e-05	BRCA2, NBN, ATM
Presynaptic phase of homologous DNA pairing and strand exchange	4	41.8×	7e-05	BRCA2, NBN, ATM, RAD51D
Diseases of DNA Double-Strand Break Repair	3	94.1×	9e-05	BRCA2, NBN, ATM
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	3	94.1×	9e-05	BRCA2, NBN, ATM
Resolution of D-Loop Structures	3	73.2×	2e-04	BRCA2, NBN, ATM
Formation of the beta-catenin:TCF transactivating complex	4	18.5×	0.001	SMARCA4, H3-3A, H3C2, MEN1
Negative Regulation of CDH1 Gene Transcription	4	18.5×	0.001	SMARCA4, CDH1, H3-3A, H3C2
Sensing of DNA Double Strand Breaks	2	146.4×	0.001	NBN, ATM
Homology Directed Repair	3	35.6×	0.001	BRCA2, NBN, ATM
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	3	35.6×	0.001	BRCA2, NBN, ATM
Impaired BRCA2 binding to RAD51	3	35.6×	0.001	BRCA2, NBN, ATM
Disease	9	4.5×	0.001	BRAF, BRCA2, CDH1, ALK, APC, MSH3, NBN, NF1 (+1 more)
Meiosis	3	32.9×	0.001	BRCA2, NBN, ATM
DNA Repair	4	15.2×	0.002	BRCA2, MSH3, NBN, ATM
DNA Double-Strand Break Repair	3	28.6×	0.002	BRCA2, NBN, ATM
TP53 Regulates Transcription of Caspase Activators and Caspases	2	73.2×	0.004	CASP10, ATM
Reproduction	3	22.0×	0.004	BRCA2, NBN, ATM
HDR through MMEJ (alt-NHEJ)	2	67.6×	0.005	BRCA2, NBN
Stabilization of p53	2	58.6×	0.006	CHEK2, ATM
DNA Damage/Telomere Stress Induced Senescence	3	18.8×	0.006	POT1, NBN, ATM

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 29 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA damage response, signal transduction by p53 class mediator	4	49.5×	3e-04	BRCA2, CHEK2, NBN, ATM
double-strand break repair via homologous recombination	5	26.9×	3e-04	BRCA2, PALB2, NBN, ATM, RAD51D
double-strand break repair	4	28.0×	0.002	BRCA2, CHEK2, NBN, ATM
negative regulation of telomere capping	2	232.4×	0.004	NBN, ATM
regulation of telomere maintenance via telomerase	2	193.7×	0.004	POT1, ATM
negative regulation of Schwann cell proliferation	2	166.0×	0.004	DICER1, NF1
negative regulation of cyclin-dependent protein serine/threonine kinase activity	2	145.3×	0.004	APC, MEN1
establishment of protein localization to telomere	2	145.3×	0.004	BRCA2, POT1
DNA damage checkpoint signaling	3	40.5×	0.004	CHEK2, NBN, ATM
positive regulation of double-strand break repair	3	35.6×	0.004	SMARCA4, NBN, ATM
telomere maintenance via recombination	2	105.7×	0.006	BRCA2, RAD51D
DNA double-strand break processing	2	105.7×	0.006	NBN, ATM
positive regulation of neuron apoptotic process	3	28.1×	0.006	CASP10, NF1, ATM
telomere maintenance	3	27.7×	0.006	NBN, ATM, RAD51D
regulation of autophagosome assembly	2	77.5×	0.010	CHEK2, ATM
inner cell mass cell proliferation	2	68.4×	0.012	BRCA2, PALB2
replicative senescence	2	68.4×	0.012	CHEK2, ATM
positive regulation of DNA-templated transcription	6	5.8×	0.014	BRCA2, SMARCA4, VHL, CHEK2, ACVR1, CDH1
cellular response to stress	2	58.1×	0.015	CHEK2, ATM
female gonad development	2	55.3×	0.015	BRCA2, IDH1
signal transduction in response to DNA damage	2	55.3×	0.015	CHEK2, ATM
positive regulation of peptidyl-serine phosphorylation	2	52.8×	0.015	BRAF, EGFR
positive regulation of telomere maintenance via telomerase	2	50.5×	0.016	POT1, ATM
negative regulation of Ras protein signal transduction	2	46.5×	0.017	LZTR1, NF1
mismatch repair	2	44.7×	0.017	MSH3, MUTYH
telomere organization	2	43.0×	0.017	H3-3A, H3C2
oocyte maturation	2	41.5×	0.017	BRCA2, H3-3A
cellular response to gamma radiation	2	41.5×	0.017	CHEK2, ATM
response to gamma radiation	2	40.1×	0.017	BRCA2, MEN1
mitotic spindle assembly checkpoint signaling	2	38.7×	0.017	APC, ATM

Therapeutics

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 10 · Phased (≥1): 11 · Undrugged: 18

Druggability breadth: 20 of 29 evidence-associated genes (69%) 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
ACVR1	MOMELOTINIB
SDHA	LINEZOLID
BRAF	VEMURAFENIB
VHL	OSIMERTINIB
CHEK2	NERATINIB
EGFR	LEVODOPA
ALK	CERITINIB
IDH1	ENASIDENIB
MEN1	LOPERAMIDE
ATM	AMIODARONE HYDROCHLORIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MEN1	475	4
EGFR	175	4
ALK	61	4
BRAF	48	4
ACVR1	39	4
ATM	35	4
CHEK2	30	4
IDH1	10	4
VHL	7	4
SMARCA4	2	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	ACVR1
FEDRATINIB	4	ACVR1, ALK, BRAF, EGFR
PACRITINIB	4	ACVR1
VANDETANIB	4	ACVR1, ALK, EGFR
LORLATINIB	4	ACVR1, ALK, EGFR
GILTERITINIB	4	ACVR1, ALK, EGFR
NINTEDANIB	4	ACVR1, ALK
DASATINIB	4	ACVR1, BRAF, EGFR
CRIZOTINIB	4	ACVR1, ALK, EGFR, VHL
LINEZOLID	4	SDHA
VEMURAFENIB	4	BRAF, EGFR
PONATINIB	4	BRAF, EGFR
SORAFENIB	4	BRAF, EGFR, MEN1
DASATINIB ANHYDROUS	4	BRAF, EGFR
RUXOLITINIB	4	ALK, BRAF
INFIGRATINIB PHOSPHATE	4	ALK, BRAF
INFIGRATINIB	4	ALK, BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF, EGFR
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	ALK, BRAF
ERLOTINIB	4	ALK, BRAF, EGFR
GEFITINIB	4	BRAF, CHEK2, EGFR
IMATINIB	4	BRAF, EGFR
OSIMERTINIB	4	ALK, EGFR, VHL
BRIGATINIB	4	ALK, CHEK2, EGFR, VHL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 11.

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

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
VHL	3,575	Binding:3482, Functional:54, ADMET:39
ALK	1,815	Binding:1801, Functional:13, ADMET:1
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
CHEK2	690	Binding:687, Functional:2, ADMET:1
IDH1	488	Binding:475, Functional:12, ADMET:1
ACVR1	299	Binding:293, Functional:4, ADMET:2
ATM	240	Binding:233, Functional:5, ADMET:2
SMARCA4	230	Binding:207, ADMET:12, Functional:11
MEN1	93	Binding:86, Functional:7
APC	24	Binding:24
CASP10	22	Binding:21, Functional:1
CDH1	18	Binding:18
DICER1	8	Binding:8
H3-3A	6	Binding:6
SDHA	3	Binding:3
NBN	2	Binding:2
POT1	1	Binding:1
MUTYH	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACVR1	2.7.10.2	non-specific protein-tyrosine kinase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
VHL	2.3.2.B13
CASP10	3.4.22.63	caspase-10
CHEK2	2.7.11.1	non-specific serine/threonine protein kinase
DICER1	3.1.26.3	ribonuclease III
EGFR	2.7.10.1	receptor protein-tyrosine kinase
ALK	2.7.10.1	receptor protein-tyrosine kinase
IDH1	1.1.1.42	isocitrate dehydrogenase (NADP+)
ATM	2.7.11.1	non-specific serine/threonine protein kinase
POLE	2.7.7.7	DNA-directed DNA polymerase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ACVR1	299
BRAF	1,442
SMARCA4	230
VHL	3,575
CHEK2	690
EGFR	6,531
ALK	1,815
IDH1	488
ATM	240

Pharmacogenomics

Cohort genes with a PharmGKB record: 29; 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)
MOMELOTINIB	4	ACVR1
FEDRATINIB	4	ACVR1, ALK, BRAF, EGFR
PACRITINIB	4	ACVR1
VANDETANIB	4	ACVR1, ALK, EGFR
LORLATINIB	4	ACVR1, ALK, EGFR
GILTERITINIB	4	ACVR1, ALK, EGFR
NINTEDANIB	4	ACVR1, ALK
DASATINIB	4	ACVR1, BRAF, EGFR
CRIZOTINIB	4	ACVR1, ALK, EGFR, VHL
LINEZOLID	4	SDHA
VEMURAFENIB	4	BRAF, EGFR
PONATINIB	4	BRAF, EGFR
SORAFENIB	4	BRAF, EGFR, MEN1
DASATINIB ANHYDROUS	4	BRAF, EGFR
RUXOLITINIB	4	ALK, BRAF
INFIGRATINIB PHOSPHATE	4	ALK, BRAF
INFIGRATINIB	4	ALK, BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF, EGFR
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	ALK, BRAF
ERLOTINIB	4	ALK, BRAF, EGFR
GEFITINIB	4	BRAF, CHEK2, EGFR
IMATINIB	4	BRAF, EGFR
OSIMERTINIB	4	ALK, EGFR, VHL
BRIGATINIB	4	ALK, CHEK2, EGFR, VHL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	ACVR1, SDHA, BRAF, VHL, CHEK2, EGFR, ALK, IDH1, MEN1, ATM
B	Phased (≥1) drug, not yet approved	1	SMARCA4
C	Druggable family + PDB, no drug	1	DICER1
D	Druggable family + AlphaFold only, no drug	1	CASP10
E	Difficult family or no structure, no drug	16	H3-3A, H3C2, BRCA2, SAMD9, POT1, CDH1, PALB2, APC, LZTR1, MSH3 (+6 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CDH1	18	EGFR
NBN	2	ATM
NF1	0	BRAF
H3-3A	6	—
H3C2	0	—
BRCA2	0	—
SAMD9	0	—
CASP10	22	—
DICER1	8	—
POT1	1	—
PALB2	0	—
APC	24	—
LZTR1	0	—
MSH3	0	—
MUTYH	1	—
POLE	0	—
PTCH2	0	—
RAD51D	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 3.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1/PHASE2	2
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04870944	PHASE1/PHASE2	RECRUITING	CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma
NCT07562971	PHASE1/PHASE2	NOT_YET_RECRUITING	Focused Ultrasound Blood-Brain Barrier Opening in Pontine Diffuse Midline Glioma to Enhance Temozolomide Therapy: Pilot Feasibility Study (FIDES)
NCT07223034	PHASE1	RECRUITING	A Study of 177Lu-PSMA-617 in People With Gliomas

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN	4	1
CHEMBL4228794	0	2

Precision-medicine subtype map (CIViC)

Drug × molecular subtype: 6 predictive associations from 7 curated evidence items; also 19 diagnostic, 2 prognostic, 1 oncogenic, 1 predisposing.

Molecular subtype	Therapy	Effect	Level	CIViC
H3-3A K28M	Dordaviprone	Sensitivity/Response	CIViC A	EID12695
GOPC::ROS1 Fusion	Entrectinib	Sensitivity/Response	CIViC C	EID11849
WEE1 Overexpression	Adavosertib	Sensitivity/Response	CIViC D	EID7242 +1
ACVR1 G328V	ALK2 Inhibitor LDN-193189	Sensitivity/Response	CIViC D	EID6092
ACVR1 G328V	MEK-1/MEKK-1 Inhibitor E6201	Sensitivity/Response	CIViC D	EID8035
ACVR1 Mutation	ALK2 Inhibitor LDN-193189	Sensitivity/Response	CIViC D	EID10141

Cohort genes: ACVR1, H3-3A, H3C2, SDHA, BRAF, BRCA2, SMARCA4, VHL, CHEK2, DICER1, POT1, CDH1, PALB2, EGFR, ALK, IDH1, APC, LZTR1, MEN1, MSH3, NF1, ATM, POLE, RAD51D, SAMD9, CASP10, MUTYH, NBN, PTCH2
Drugs: LUTETIUM LU-177 VIPIVOTIDE TETRAXETAN, Dordaviprone, Entrectinib