Colorectal cancer, susceptibility to, 3

Summary

Colorectal cancer, susceptibility to, 3 (MONDO:0012820) is a cancer with 1 cohort gene.

At a glance

• Classification: Cancer
• Cohort genes: 1
• ClinVar variants: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	colorectal cancer, susceptibility to, 3
Mondo ID	MONDO:0012820
OMIM	612229
UMLS	C2677123
MedGen	436866
GARD	0027816
Is cancer (heuristic)	yes

Also known as: colorectal cancer caused by mutation in SMAD7 · colorectal cancer, susceptibility to, 3 · colorectal cancer, susceptibility to, type 3 · CRCS3 · SMAD7 colorectal cancer

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neoplastic syndrome › colorectal cancer, susceptibility to, 3

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, 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, tumor predisposition syndrome 2, 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

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
6725	NM_005904.4(SMAD7):c.743-5183=	SMAD7	risk factor	no assertion criteria provided
2247899	NM_005904.4(SMAD7):c.166G>A (p.Gly56Ser)	SMAD7	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 0 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
SMAD7	Limited	Autosomal dominant	colorectal cancer, susceptibility to, 3	2

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
SMAD7	HGNC:6773	ENSG00000101665	O15105	SMAD family member 7	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SMAD7	SMAD family member 7	Antagonist of signaling by TGF-beta (transforming growth factor) type 1 receptor superfamily members; has been shown to inhibit TGF-beta (Transforming growth factor) and activin signaling by associating with their receptors thus preventing…

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)
SMAD7	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_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
aorta	1
popliteal artery	1
tibial artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SMAD7	265	ubiquitous	marker	popliteal artery, tibial artery, aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD7	3,229

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SMAD7	O15105	7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. 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
Downregulation of TGF-beta receptor signaling	1	407.9×	0.011	SMAD7
Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer	1	368.4×	0.011	SMAD7
Downregulation of SMAD2/3:SMAD4 transcriptional activity	1	368.4×	0.011	SMAD7
Signaling by BMP	1	356.9×	0.011	SMAD7
TGF-beta receptor signaling activates SMADs	1	326.3×	0.011	SMAD7
SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription	1	308.6×	0.011	SMAD7
Signaling by TGF-beta Receptor Complex	1	200.3×	0.015	SMAD7
Interferon gamma signaling	1	125.5×	0.015	SMAD7
Deubiquitination	1	124.1×	0.015	SMAD7
UCH proteinases	1	124.1×	0.015	SMAD7
Interferon Signaling	1	120.2×	0.015	SMAD7
Signaling by TGFB family members	1	115.3×	0.015	SMAD7
Ub-specific processing proteases	1	53.1×	0.030	SMAD7
Cytokine Signaling in Immune system	1	40.8×	0.037	SMAD7
RNA Polymerase II Transcription	1	22.5×	0.062	SMAD7
Post-translational protein modification	1	19.2×	0.068	SMAD7
Gene expression (Transcription)	1	17.8×	0.069	SMAD7
Generic Transcription Pathway	1	15.1×	0.077	SMAD7
Immune System	1	13.0×	0.085	SMAD7
Metabolism of proteins	1	12.4×	0.085	SMAD7
Signal Transduction	1	10.2×	0.098	SMAD7

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
positive regulation of chondrocyte hypertrophy	1	16852.0×	0.001	SMAD7
beta-catenin destruction complex disassembly	1	16852.0×	0.001	SMAD7
negative regulation of T-helper 17 type immune response	1	8426.0×	0.001	SMAD7
protein-containing complex disassembly	1	5617.3×	0.001	SMAD7
response to laminar fluid shear stress	1	4213.0×	0.001	SMAD7
negative regulation of chondrocyte proliferation	1	4213.0×	0.001	SMAD7
regulation of ventricular cardiac muscle cell membrane depolarization	1	2808.7×	0.002	SMAD7
negative regulation of T cell cytokine production	1	2407.4×	0.002	SMAD7
negative regulation of T-helper 17 cell differentiation	1	1872.4×	0.002	SMAD7
regulation of epithelial to mesenchymal transition	1	1532.0×	0.002	SMAD7
negative regulation of activin receptor signaling pathway	1	1404.3×	0.002	SMAD7
obsolete negative regulation of transcription by competitive promoter binding	1	1296.3×	0.002	SMAD7
adherens junction assembly	1	1296.3×	0.002	SMAD7
positive regulation of cell-cell adhesion mediated by cadherin	1	1296.3×	0.002	SMAD7
protein-containing complex localization	1	991.3×	0.002	SMAD7
regulation of cardiac muscle contraction	1	887.0×	0.002	SMAD7
SMAD protein signal transduction	1	732.7×	0.003	SMAD7
ventricular cardiac muscle tissue morphogenesis	1	702.2×	0.003	SMAD7
artery morphogenesis	1	674.1×	0.003	SMAD7
negative regulation of ossification	1	624.1×	0.003	SMAD7
negative regulation of SMAD protein signal transduction	1	601.9×	0.003	SMAD7
ureteric bud development	1	455.5×	0.003	SMAD7
ventricular septum morphogenesis	1	432.1×	0.004	SMAD7
negative regulation of epithelial to mesenchymal transition	1	411.0×	0.004	SMAD7
negative regulation of BMP signaling pathway	1	290.6×	0.005	SMAD7
positive regulation of proteasomal ubiquitin-dependent protein catabolic process	1	210.7×	0.006	SMAD7
negative regulation of transforming growth factor beta receptor signaling pathway	1	173.7×	0.007	SMAD7
transforming growth factor beta receptor signaling pathway	1	159.0×	0.008	SMAD7
cellular response to leukemia inhibitory factor	1	159.0×	0.008	SMAD7
anatomical structure morphogenesis	1	139.3×	0.008	SMAD7

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SMAD7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	SMAD7

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)
SMAD7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.