Rhabdoid tumor predisposition syndrome 2

Summary

Rhabdoid tumor predisposition syndrome 2 (MONDO:0013224) is a cancer caused by SMARCA4 (GenCC Definitive), with 4 cohort genes (2 CIViC-evidence somatic drivers; 5,245 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: SMARCA4 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 5,245

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	rhabdoid tumor predisposition syndrome 2
Mondo ID	MONDO:0013224
MeSH	C567643
OMIM	613325
DOID	DOID:0060997
NCIT	C178394
UMLS	C2750074
MedGen	413749
GARD	0018319
Is cancer (heuristic)	yes

Also known as: familial rhabdoid tumor caused by mutation in SMARCA4 · familial rhabdoid tumour caused by mutation in SMARCA4 · rhabdoid tumor predisposition syndrome 2 · rhabdoid tumor predisposition syndrome type 2 · rhabdoid tumour predisposition syndrome type 2 · RTPS2 · SMARCA4 familial rhabdoid tumor · SMARCA4 familial rhabdoid tumour

Data availability: 5,245 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › neoplastic disease or syndrome › neoplasm › embryonal neoplasm › rhabdoid tumor › familial rhabdoid tumor › rhabdoid tumor predisposition syndrome 2

Related subtypes (1): rhabdoid tumor predisposition syndrome 1

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:

268 likely benign, 251 uncertain significance, 41 conflicting classifications of pathogenicity, 21 pathogenic, 8 benign, 7 benign/likely benign, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068242	NM_003072.5(SMARCA4):c.3547-1G>A	SMARCA4	Pathogenic	criteria provided, single submitter
1070370	NM_003072.5(SMARCA4):c.2149G>T (p.Glu717Ter)	SMARCA4	Pathogenic	criteria provided, single submitter
1072182	NM_003072.5(SMARCA4):c.2826G>A (p.Trp942Ter)	SMARCA4	Pathogenic	criteria provided, single submitter
1072302	NM_003072.5(SMARCA4):c.574del (p.Arg192fs)	SMARCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1072497	NM_003072.5(SMARCA4):c.3129del (p.Lys1044fs)	SMARCA4	Pathogenic	criteria provided, single submitter
1072687	NC_000019.9:g.(?11094822)(11172498_?)del	SMARCA4	Pathogenic	criteria provided, single submitter
1072688	NC_000019.9:g.(?11094828)(11152246_?)del	SMARCA4	Pathogenic	criteria provided, single submitter
1072689	NC_000019.9:g.(?11101816)(11152246_?)del	SMARCA4	Pathogenic	criteria provided, single submitter
1073889	NM_003072.5(SMARCA4):c.4077T>A (p.Cys1359Ter)	SMARCA4	Pathogenic	criteria provided, single submitter
1074336	NM_003072.5(SMARCA4):c.336dup (p.Met113fs)	SMARCA4	Pathogenic	criteria provided, single submitter
1360114	NM_003072.5(SMARCA4):c.2780del (p.Phe927fs)	SMARCA4	Pathogenic	criteria provided, single submitter
1360962	NM_003072.5(SMARCA4):c.917_941del (p.Gln306fs)	SMARCA4	Pathogenic	criteria provided, single submitter
1382120	NM_003072.5(SMARCA4):c.1378C>T (p.Gln460Ter)	SMARCA4	Pathogenic	criteria provided, single submitter
139439	NM_003072.5(SMARCA4):c.3533G>A (p.Trp1178Ter)	SMARCA4	Pathogenic	criteria provided, single submitter
139440	NM_003072.5(SMARCA4):c.4170+1G>A	SMARCA4	Pathogenic	no assertion criteria provided
139441	NM_003072.5(SMARCA4):c.643C>T (p.Gln215Ter)	SMARCA4	Pathogenic	no assertion criteria provided
139442	NM_003072.5(SMARCA4):c.2617-3C>G	SMARCA4	Pathogenic	no assertion criteria provided
139443	NM_003072.5(SMARCA4):c.3239G>A (p.Gly1080Asp)	SMARCA4	Pathogenic	no assertion criteria provided
1396816	NM_003072.5(SMARCA4):c.2838del (p.Phe947fs)	SMARCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1397435	NM_003072.5(SMARCA4):c.3228C>G (p.Tyr1076Ter)	SMARCA4	Pathogenic	criteria provided, single submitter
1402988	NM_003072.5(SMARCA4):c.3013C>T (p.Arg1005Ter)	SMARCA4	Pathogenic	criteria provided, multiple submitters, no conflicts
1065963	NM_003072.5(SMARCA4):c.3546+1G>A	SMARCA4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066568	NM_003072.5(SMARCA4):c.3774+2T>A	SMARCA4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068028	NM_003072.5(SMARCA4):c.2263A>G (p.Lys755Glu)	SMARCA4	Likely pathogenic	criteria provided, single submitter
1068275	NM_003072.5(SMARCA4):c.87_222+48del	SMARCA4	Likely pathogenic	criteria provided, single submitter
1002498	NM_003072.5(SMARCA4):c.2441C>T (p.Thr814Met)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1006102	NM_003072.5(SMARCA4):c.4171-1807G>T	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1012922	NM_003072.5(SMARCA4):c.1762-2A>G	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020123	NM_003072.5(SMARCA4):c.702_719dup (p.229GP[11])	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1020994	NM_003072.5(SMARCA4):c.1645C>T (p.Arg549Cys)	SMARCA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 10 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
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
SMARCB1	Act	ATRT,MBL,NBL,PANET,PAST	CIViC #5356

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
SMARCA4	Definitive	Autosomal dominant	rhabdoid tumor predisposition syndrome 2	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
SMARCB1	Orphanet:1465	Coffin-Siris syndrome
SMARCB1	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCB1	Orphanet:2495	Meningioma
SMARCB1	Orphanet:263662	Familial multiple meningioma
SMARCB1	Orphanet:93921	Full schwannomatosis
SMARCB1	Orphanet:99966	Atypical teratoid rhabdoid tumor

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	gencc,clinvar
SMARCB1	HGNC:11103	ENSG00000099956	Q12824	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	clinvar
ANGPTL8	HGNC:24933	ENSG00000130173	Q6UXH0	Angiopoietin-like protein 8	clinvar
HCCS-DT	HGNC:55698	ENSG00000234129		HCCS divergent transcript	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).
SMARCB1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	Core component of the BAF (hSWI/SNF) complex.
ANGPTL8	Angiopoietin-like protein 8	Hormone that acts as a blood lipid regulator by regulating serum triglyceride levels.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SMARCB1	Other/Unknown	no		SNF5, Sfh1/SNF5, INI1_DNA-bd
ANGPTL8	Other/Unknown	no		ANGPTL8
HCCS-DT	Other/Unknown	no

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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	2
ganglionic eminence	2
primordial germ cell in gonad	2
cervix squamous epithelium	1
embryo	1
liver	1
right lobe of liver	1
colonic epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
SMARCB1	214	ubiquitous	marker	embryo, ganglionic eminence, cortical plate
ANGPTL8	153	tissue_specific	yes	right lobe of liver, liver, primordial germ cell in gonad
HCCS-DT	128		yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, colonic epithelium

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMARCA4	8,138
SMARCB1	5,083
ANGPTL8	407
HCCS-DT	0

Intra-cohort edges

A	B	Sources
SMARCA4	SMARCB1	intact, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMARCA4	P51532	31
SMARCB1	Q12824	17

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANGPTL8	Q6UXH0	85.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the canonical BAF (cBAF) complex	2	423.0×	9e-05	SMARCA4, SMARCB1
Formation of the polybromo-BAF (pBAF) complex	2	423.0×	9e-05	SMARCA4, SMARCB1
Formation of the embryonic stem cell BAF (esBAF) complex	2	400.7×	9e-05	SMARCA4, SMARCB1
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	2	304.5×	1e-04	SMARCA4, SMARCB1
Regulation of endogenous retroelements	2	245.6×	2e-04	SMARCA4, SMARCB1
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	2	200.3×	2e-04	SMARCA4, SMARCB1
Regulation of MITF-M-dependent genes involved in pigmentation	2	177.1×	2e-04	SMARCA4, SMARCB1
MITF-M-dependent gene expression	2	120.8×	4e-04	SMARCA4, SMARCB1
RMTs methylate histone arginines	2	97.6×	5e-04	SMARCA4, SMARCB1
Transcriptional regulation by RUNX1	2	97.6×	5e-04	SMARCA4, SMARCB1
Regulation of endogenous retroelements by Piwi-interacting RNAs (piRNAs)	2	78.5×	7e-04	SMARCA4, SMARCB1
MITF-M-regulated melanocyte development	2	76.1×	7e-04	SMARCA4, SMARCB1
Chromatin organization	2	54.4×	0.001	SMARCA4, SMARCB1
Chromatin modifying enzymes	2	48.2×	0.001	SMARCA4, SMARCB1
Epigenetic regulation of gene expression	2	47.6×	0.001	SMARCA4, SMARCB1
Formation of the non-canonical BAF (ncBAF) complex	1	223.9×	0.010	SMARCA4
Assembly of active LPL and LIPC lipase complexes	1	200.3×	0.011	ANGPTL8
RNA Polymerase II Transcription	2	15.0×	0.011	SMARCA4, SMARCB1
Plasma lipoprotein remodeling	1	158.6×	0.012	ANGPTL8
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.015	SMARCA4
Interleukin-7 signaling	1	105.7×	0.015	SMARCA4
Gene expression (Transcription)	2	11.9×	0.015	SMARCA4, SMARCB1
Plasma lipoprotein assembly, remodeling, and clearance	1	76.1×	0.020	ANGPTL8
Generic Transcription Pathway	2	10.1×	0.020	SMARCA4, SMARCB1
Developmental Biology	2	9.6×	0.020	SMARCA4, SMARCB1
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	1	48.8×	0.028	SMARCA4
Formation of the beta-catenin:TCF transactivating complex	1	40.1×	0.031	SMARCA4
Negative Regulation of CDH1 Gene Transcription	1	40.1×	0.031	SMARCA4
TCF dependent signaling in response to WNT	1	39.2×	0.031	SMARCA4
Signaling by WNT	1	37.3×	0.032	SMARCA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of glucose mediated signaling pathway	2	3744.9×	3e-06	SMARCA4, SMARCB1
RNA polymerase I preinitiation complex assembly	2	2246.9×	5e-06	SMARCA4, SMARCB1
positive regulation of transcription of nucleolar large rRNA by RNA polymerase I	2	1021.3×	2e-05	SMARCA4, SMARCB1
host-mediated activation of viral transcription	2	591.3×	4e-05	SMARCA4, SMARCB1
nucleosome disassembly	2	535.0×	4e-05	SMARCA4, SMARCB1
regulation of G0 to G1 transition	2	449.4×	5e-05	SMARCA4, SMARCB1
regulation of nucleotide-excision repair	2	401.2×	5e-05	SMARCA4, SMARCB1
regulation of mitotic metaphase/anaphase transition	2	330.4×	7e-05	SMARCA4, SMARCB1
positive regulation of T cell differentiation	2	303.6×	7e-05	SMARCA4, SMARCB1
transcription initiation-coupled chromatin remodeling	2	255.3×	8e-05	SMARCA4, SMARCB1
positive regulation of myoblast differentiation	2	244.2×	8e-05	SMARCA4, SMARCB1
positive regulation of stem cell population maintenance	2	229.3×	8e-05	SMARCA4, SMARCB1
positive regulation of double-strand break repair	2	229.3×	8e-05	SMARCA4, SMARCB1
regulation of G1/S transition of mitotic cell cycle	2	204.3×	1e-04	SMARCA4, SMARCB1
positive regulation of cell differentiation	2	178.3×	1e-04	SMARCA4, SMARCB1
single stranded viral RNA replication via double stranded DNA intermediate	1	5617.3×	5e-04	SMARCB1
regulation of lipoprotein metabolic process	1	1872.4×	0.001	ANGPTL8
chromatin remodeling	2	48.6×	0.001	SMARCA4, SMARCB1
DNA integration	1	702.2×	0.003	SMARCB1
nervous system development	2	30.6×	0.003	SMARCA4, SMARCB1
positive regulation of protein processing	1	401.2×	0.005	ANGPTL8
hepatocyte differentiation	1	401.2×	0.005	SMARCB1
positive regulation of signal transduction by p53 class mediator	1	401.2×	0.005	SMARCA4
neural retina development	1	312.1×	0.006	SMARCA4
negative regulation of androgen receptor signaling pathway	1	312.1×	0.006	SMARCA4
blastocyst hatching	1	181.2×	0.009	SMARCB1
triglyceride homeostasis	1	160.5×	0.010	ANGPTL8
cell maturation	1	147.8×	0.011	ANGPTL8
regulation of lipid metabolic process	1	144.0×	0.011	ANGPTL8
positive regulation of Wnt signaling pathway	1	127.7×	0.011	SMARCA4

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 4 evidence-associated genes (75%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMARCA4	2	2
SMARCB1	0	0
ANGPTL8	0	0
HCCS-DT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	SMARCA4
CAMIBIRSTAT	2	SMARCA4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SMARCA4	230	Binding:207, ADMET:12, Functional:11
SMARCB1	7	Binding:7
ANGPTL8	1	Binding:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SMARCA4	230

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Drug repurposing candidates

2 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)
MOLIBRESIB	2	SMARCA4
CAMIBIRSTAT	2	SMARCA4

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	1	SMARCA4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SMARCB1, ANGPTL8, HCCS-DT

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SMARCB1	7	SMARCA4
ANGPTL8	1	—
HCCS-DT	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.