Tumor predisposition syndrome 2

Summary

Tumor predisposition syndrome 2 (MONDO:0859267) is a cancer caused by MBD4 (GenCC Strong), with 1 cohort gene (1 CIViC-evidence somatic driver; 25 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MBD4 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 25

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	tumor predisposition syndrome 2
Mondo ID	MONDO:0859267
OMIM	619975
Orphanet	661526
UMLS	C5774186
MedGen	1823959
GARD	0026684
Is cancer (heuristic)	yes

Also known as: MANS · MBD4-associated neoplasia syndrome · MBD4-related recessive tumor predisposition syndrome · TPDS2

Data availability: 25 ClinVar variants · 3 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 › tumor predisposition syndrome 2

Related subtypes (116): mosaic variegated aneuploidy syndrome, tuberous sclerosis, hereditary breast ovarian cancer syndrome, hereditary multiple osteochondromas, nevoid basal cell carcinoma syndrome, leukemia, chronic lymphocytic, susceptibility to, 2, blue rubber bleb nevus, cherubism, Beckwith-Wiedemann syndrome, multiple self-healing squamous epithelioma, erythroleukemia, familial, susceptibility to, goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, hyperparathyroidism 2 with jaw tumors, Kaposi sarcoma, susceptibility to, hereditary leiomyomatosis and renal cell cancer, susceptibility to uveal melanoma, melanoma and neural system tumor syndrome, nasopharyngeal carcinoma, susceptibility to, 2, WAGR syndrome, neuroblastoma, susceptibility to, 1, Rothmund-Thomson syndrome, mismatch repair cancer syndrome 1, Wiskott-Aldrich syndrome, N syndrome, hereditary thrombocytopenia and hematologic cancer predisposition syndrome, prostate cancer/brain cancer susceptibility, Brooke-Spiegler syndrome, pancreatic cancer, susceptibility to, 1, Carney-Stratakis syndrome, nasopharyngeal carcinoma, susceptibility to, 1, ovarian cancer, susceptibility to, 1, colorectal cancer, susceptibility to, 1, lung cancer susceptibility 1, leukemia, chronic lymphocytic, susceptibility to, 1, Kostmann syndrome, colorectal cancer, susceptibility to, 2, colorectal cancer, susceptibility to, 3, colorectal cancer, susceptibility to, 5, colorectal cancer, susceptibility to, 6, colorectal cancer, susceptibility to, 7, leukemia, chronic lymphocytic, susceptibility to, 3, leukemia, chronic lymphocytic, susceptibility to, 4, leukemia, chronic lymphocytic, susceptibility to, 5, lung cancer susceptibility 3, colorectal cancer, susceptibility to, 8, colorectal cancer, susceptibility to, 9, colorectal cancer, susceptibility to, 10, colorectal cancer, susceptibility to, 11, lung cancer susceptibility 4, neuroblastoma, susceptibility to, 3, neuroblastoma, susceptibility to, 4, neuroblastoma, susceptibility to, 5, neuroblastoma, susceptibility to, 6, leukemia, acute lymphocytic, susceptibility to, 1, leukemia, acute lymphocytic, susceptibility to, 2, lung cancer susceptibility 5, BAP1-related tumor predisposition syndrome, familial cutaneous telangiectasia and oropharyngeal predisposition cancer syndrome, Maffucci syndrome, basal cell carcinoma, susceptibility to, 7, colorectal cancer, susceptibility to, 12, leukemia, acute lymphoblastic, susceptibility to, 3, cholangiocarcinoma, susceptibility to, progeroid features-hepatocellular carcinoma predisposition syndrome, neuroblastoma, susceptibility to, 7, DDX41-related hematologic malignancy predisposition syndrome, nasopharyngeal carcinoma, susceptibility to, 3, familial isolated hyperparathyroidism, intestinal polyposis syndrome, dyskeratosis congenita, familial rhabdoid tumor, multiple endocrine neoplasia, hereditary pheochromocytoma-paraganglioma, PTEN hamartoma tumor syndrome, familial multiple fibrofolliculoma, hereditary retinoblastoma, familial atypical multiple mole melanoma syndrome, hereditary nonpolyposis colon cancer, Li-Fraumeni syndrome, Cobb syndrome, neurofibromatosis, susceptibility to familial cutaneous melanoma, pancreatic cancer, susceptibility to, 5, leukemia, acute myeloid, susceptibility to, diffuse gastric and lobular breast cancer syndrome with or without cleft lip and/or palate, glioma susceptibility, hemangioma, capillary infantile, susceptibility to, CDH1-related diffuse gastric and lobular breast cancer syndrome, NTHL1-deficiency tumor predisposition syndrome, SAMD9-related spectrum and myeloid neoplasm risk, neuroblastoma, susceptibility to, 2, BARD1-related cancer predisposition, BRCA1-related cancer predisposition, BRCA2-related cancer predisposition, ATM-related cancer predisposition, CHEK2-related cancer predisposition, PALB2-related cancer predisposition, RAD51C-related cancer predisposition, RAD51D-related cancer predisposition, Li-fraumeni-like syndrome, breast cancer, familial, susceptibility to, 1, breast cancer, familial, susceptibility to, 2, breast cancer, familial, susceptibility to, 3, colorectal cancer, susceptibility to, 4, colorectal cancer, susceptibility to, on chromosome 15, ovarian cancer, familial, susceptibility to, 1, ovarian cancer, familial, susceptibility to, 2, ovarian cancer, familial, susceptibility to, 3, inherited hematologic cancer-predisposing syndrome, mosaic neurofibromatosis/schwannomatosis, prostate cancer, hereditary, X-linked 3, follicular lymphoma, susceptibility to, GPR161-related medulloblastoma predisposition, SAMD9L-related spectrum and myeloid neoplasm risk, HAVCR2-related cancer predisposition, EGLN1-related erythrocytosis and pheochromocytoma/paraganglioma predisposition

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

25 retrieved; paginated sample, class counts are floors:

10 pathogenic, 8 pathogenic/likely pathogenic, 3 uncertain significance, 3 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1338644	NM_001276270.2(MBD4):c.939dup (p.Glu314fs)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700250	NM_003925.2:c.1699_1701del	MBD4	Pathogenic	no assertion criteria provided
1700251	NM_001276270.2(MBD4):c.1544-1G>T	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700253	NM_001276270.2(MBD4):c.217C>T (p.Gln73Ter)	MBD4	Pathogenic	criteria provided, multiple submitters, no conflicts
1700254	NM_001276270.2(MBD4):c.1670T>A (p.Leu557Ter)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1700255	NM_001276270.2(MBD4):c.612_615del (p.Ser205fs)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1976297	NM_001276270.2(MBD4):c.1213_1216del (p.Arg405fs)	MBD4	Pathogenic	criteria provided, multiple submitters, no conflicts
2107332	NM_001276270.2(MBD4):c.614_615del (p.Leu204_Ser205insTer)	MBD4	Pathogenic	criteria provided, multiple submitters, no conflicts
2203429	NM_001276270.2(MBD4):c.942_945del (p.Glu314fs)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2725154	NM_001276270.2(MBD4):c.1425del (p.Leu476fs)	MBD4	Pathogenic	criteria provided, multiple submitters, no conflicts
2776590	NM_001276270.2(MBD4):c.962C>G (p.Ser321Ter)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2783108	NM_001276270.2(MBD4):c.541C>T (p.Arg181Ter)	MBD4	Pathogenic	criteria provided, multiple submitters, no conflicts
2798240	NM_001276270.2(MBD4):c.229dup (p.Thr77fs)	MBD4	Pathogenic	criteria provided, multiple submitters, no conflicts
2807074	NM_001276270.2(MBD4):c.939del (p.Glu314fs)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3678782	NM_001276270.2(MBD4):c.1617C>A (p.Tyr539Ter)	MBD4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4052217	NM_001276270.2(MBD4):c.1237dup (p.Ser413fs)	MBD4	Pathogenic	criteria provided, multiple submitters, no conflicts
4813000	NM_001276270.2(MBD4):c.916_919del (p.Glu306fs)	MBD4	Pathogenic	criteria provided, single submitter
4813029	NM_001276270.2(MBD4):c.1475_1476del (p.Asp492fs)	MBD4	Pathogenic	criteria provided, single submitter
3643354	NM_001276270.2(MBD4):c.104+1G>A	MBD4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1879591	NM_001276270.2(MBD4):c.572C>T (p.Pro191Leu)	MBD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2869314	NM_001276270.2(MBD4):c.1393+2T>C	MBD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3543746	NM_001276270.2(MBD4):c.76C>G (p.Leu26Val)	MBD4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1338066	NM_001276270.2(MBD4):c.1160C>T (p.Ser387Leu)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
2712037	NM_001276270.2(MBD4):c.1636G>A (p.Glu546Lys)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3543756	NM_001276270.2(MBD4):c.229A>G (p.Thr77Ala)	MBD4	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
MBD4			CIViC #7084

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
MBD4	Strong	Autosomal recessive	tumor predisposition syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MBD4	Orphanet:661526	MBD4-related tumor predisposition syndrome

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
MBD4	HGNC:6919	ENSG00000129071	O95243	Methyl-CpG-binding domain protein 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MBD4	Methyl-CpG-binding domain protein 4	Mismatch-specific DNA N-glycosylase involved in DNA repair.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MBD4	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA_glycosylase, DNA-bd_dom_sf

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
oocyte	1
pylorus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MBD4	299	ubiquitous	marker	secondary oocyte, oocyte, pylorus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MBD4	1,362

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MBD4	O95243	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. 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
Resolution of Abasic Sites (AP sites)	1	1142.0×	0.002	MBD4
Displacement of DNA glycosylase by APEX1	1	1038.2×	0.002	MBD4
Depyrimidination	1	951.7×	0.002	MBD4
Base-Excision Repair, AP Site Formation	1	878.5×	0.002	MBD4
Base Excision Repair	1	713.8×	0.002	MBD4
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	1	184.2×	0.006	MBD4
Cleavage of the damaged pyrimidine	1	184.2×	0.006	MBD4
DNA Repair	1	98.5×	0.010	MBD4

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
depyrimidination	1	1872.4×	0.002	MBD4
response to estradiol	1	198.3×	0.008	MBD4
DNA repair	1	63.8×	0.016	MBD4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MBD4	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
MBD4	1	Functional:1

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

0 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.

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	1	MBD4

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)
MBD4	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.