medulloblastoma SHH activated and TP53 wild-type

Summary

medulloblastoma SHH activated and TP53 wild-type (MONDO:0956965) is a disease with 2 cohort genes.

At a glance

• Cohort genes: 2
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	medulloblastoma SHH activated and TP53 wild-type
Mondo ID	MONDO:0956965
DOID	DOID:0080705
NCIT	C129443
GARD	0026769
Is cancer (heuristic)	no

Data availability: 3 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › cerebellar disorder › cerebellar neoplasm › medulloblastoma › medulloblastoma SHH activated › medulloblastoma SHH activated and TP53 wild-type

Related subtypes (1): medulloblastoma SHH activated and TP53 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

3 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
127838	NM_001048174.2(MUTYH):c.1350GGA[1] (p.Glu452del)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5296	NM_001048174.2(MUTYH):c.228C>A (p.Tyr76Ter)	MUTYH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4687853	NM_000059.4(BRCA2):c.9325C>G (p.Leu3109Val)	BRCA2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare 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
MUTYH	Orphanet:247798	MUTYH-related polyposis
MUTYH	Orphanet:440437	Familial colorectal cancer Type X

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
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
MUTYH	HGNC:7527	ENSG00000132781	Q9UIF7	Adenine DNA glycosylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
MUTYH	Adenine DNA glycosylase	Involved in oxidative DNA damage repair.

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)
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
MUTYH	Other/Unknown	no		NUDIX_hydrolase_dom, HhH_motif, HhH-GPD_domain

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
male germ line stem cell (sensu Vertebrata) in testis	1
secondary oocyte	1
ventricular zone	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
MUTYH	134	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRCA2	4,839
MUTYH	1,815

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRCA2	P51587	14
MUTYH	Q9UIF7	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 32. 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
Defective MUTYH substrate binding	1	5710.0×	0.003	MUTYH
Defective MUTYH substrate processing	1	5710.0×	0.003	MUTYH
Impaired BRCA2 translocation to the nucleus	1	1903.3×	0.004	BRCA2
Impaired BRCA2 binding to SEM1 (DSS1)	1	1903.3×	0.004	BRCA2
Displacement of DNA glycosylase by APEX1	1	519.1×	0.009	MUTYH
Defective homologous recombination repair (HRR) due to PALB2 loss of function	1	475.8×	0.009	BRCA2
HDR through MMEJ (alt-NHEJ)	1	439.2×	0.009	BRCA2
Diseases of DNA Double-Strand Break Repair	1	407.9×	0.009	BRCA2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	1	407.9×	0.009	BRCA2
Resolution of D-Loop Structures	1	317.2×	0.010	BRCA2
Diseases of DNA repair	1	285.5×	0.010	BRCA2
Impaired BRCA2 binding to PALB2	1	228.4×	0.010	BRCA2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	1	211.5×	0.010	BRCA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	1	211.5×	0.010	BRCA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	1	211.5×	0.010	BRCA2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	1	196.9×	0.010	BRCA2
Homologous DNA Pairing and Strand Exchange	1	190.3×	0.010	BRCA2
Homology Directed Repair	1	154.3×	0.010	BRCA2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1	154.3×	0.010	BRCA2
Impaired BRCA2 binding to RAD51	1	154.3×	0.010	BRCA2
Resolution of D-loop Structures through Holliday Junction Intermediates	1	150.3×	0.010	BRCA2
Meiosis	1	142.8×	0.010	BRCA2
Presynaptic phase of homologous DNA pairing and strand exchange	1	135.9×	0.010	BRCA2
DNA Double-Strand Break Repair	1	124.1×	0.011	BRCA2
Recognition and association of DNA glycosylase with site containing an affected purine	1	102.0×	0.012	MUTYH
Cleavage of the damaged purine	1	102.0×	0.012	MUTYH
Reproduction	1	95.2×	0.012	BRCA2
HDR through Homologous Recombination (HRR)	1	95.2×	0.012	BRCA2
Meiotic recombination	1	64.9×	0.017	BRCA2
DNA Repair	1	49.2×	0.022	BRCA2

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
mitotic recombination-dependent replication fork processing	1	4213.0×	0.006	BRCA2
depurination	1	2106.5×	0.006	MUTYH
negative regulation of mammary gland epithelial cell proliferation	1	1685.2×	0.006	BRCA2
establishment of protein localization to telomere	1	1053.2×	0.006	BRCA2
response to UV-C	1	842.6×	0.006	BRCA2
telomere maintenance via recombination	1	766.0×	0.006	BRCA2
regulation of DNA damage checkpoint	1	561.7×	0.006	BRCA2
inner cell mass cell proliferation	1	495.6×	0.006	BRCA2
negative regulation of necroptotic process	1	495.6×	0.006	MUTYH
centrosome duplication	1	468.1×	0.006	BRCA2
response to X-ray	1	443.5×	0.006	BRCA2
female gonad development	1	401.2×	0.006	BRCA2
mismatch repair	1	324.1×	0.006	MUTYH
hematopoietic stem cell proliferation	1	324.1×	0.006	BRCA2
oocyte maturation	1	300.9×	0.006	BRCA2
male meiosis I	1	290.6×	0.006	BRCA2
response to gamma radiation	1	290.6×	0.006	BRCA2
intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator	1	247.8×	0.007	BRCA2
base-excision repair	1	234.1×	0.007	MUTYH
positive regulation of mitotic cell cycle	1	234.1×	0.007	BRCA2
regulation of cytokinesis	1	210.7×	0.007	BRCA2
cellular response to ionizing radiation	1	205.5×	0.007	BRCA2
nucleotide-excision repair	1	191.5×	0.007	BRCA2
DNA damage response, signal transduction by p53 class mediator	1	179.3×	0.007	BRCA2
cellular senescence	1	147.8×	0.009	BRCA2
double-strand break repair	1	101.5×	0.012	BRCA2
double-strand break repair via homologous recombination	1	78.0×	0.015	BRCA2
brain development	1	39.8×	0.029	BRCA2
DNA repair	1	31.9×	0.034	MUTYH
spermatogenesis	1	17.6×	0.060	BRCA2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRCA2	0	0
MUTYH	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MUTYH	1	Functional:1

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).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
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	2	BRCA2, MUTYH

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRCA2	0	—
MUTYH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.