Polyposis syndrome, hereditary mixed, 1

Summary

Polyposis syndrome, hereditary mixed, 1 (MONDO:0042486) is a disease caused by GREM1 (GenCC Strong), with 5 cohort genes and 1 clinical trial.

At a glance

• Causal gene: GREM1 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 18
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polyposis syndrome, hereditary mixed, 1
Mondo ID	MONDO:0042486
OMIM	601228
DOID	DOID:0111685
UMLS	C1832587
MedGen	331320
GARD	0025848
Is cancer (heuristic)	no

Also known as: HMPS1 · polyposis syndrome, hereditary mixed 1 · polyposis syndrome, hereditary mixed, 1

Data availability: 18 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › digestive system disorder › hereditary mixed polyposis syndrome › polyposis syndrome, hereditary mixed, 1

Related subtypes (1): polyposis syndrome, hereditary mixed, 2

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

18 retrieved; paginated sample, class counts are floors:

8 likely pathogenic, 6 uncertain significance, 3 pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
38805	NC_000015.10:g.32672737_32712558dup	ARHGAP11A-SCG5	Pathogenic	no assertion criteria provided
266706	NM_000059.4(BRCA2):c.2514del (p.Lys838fs)	BRCA2	Pathogenic	reviewed by expert panel
1042674	NM_001903.5(CTNNA1):c.1479del (p.Lys493fs)	CTNNA1	Pathogenic	criteria provided, single submitter
1703198	NM_007294.4(BRCA1):c.1015_1016del (p.Lys339fs)	BRCA1	Likely pathogenic	no assertion criteria provided
1703199	NM_000059.4(BRCA2):c.3935del (p.Asn1312fs)	BRCA2	Likely pathogenic	no assertion criteria provided
1703200	NM_000059.4(BRCA2):c.4468del (p.Ile1490fs)	BRCA2	Likely pathogenic	no assertion criteria provided
1703201	NM_000059.4(BRCA2):c.4997del (p.Asn1666fs)	BRCA2	Likely pathogenic	no assertion criteria provided
1703203	NM_000059.4(BRCA2):c.9799_9800del (p.Lys3267fs)	BRCA2	Likely pathogenic	no assertion criteria provided
1703208	NM_000059.4(BRCA2):c.3440del (p.Asn1147fs)	BRCA2	Likely pathogenic	no assertion criteria provided
1700651	NM_001903.5(CTNNA1):c.235del (p.Ile79fs)	CTNNA1	Likely pathogenic	no assertion criteria provided
1700653	NM_001903.5(CTNNA1):c.1559del (p.Leu520fs)	CTNNA1	Likely pathogenic	no assertion criteria provided
645011	NM_001903.5(CTNNA1):c.339T>A (p.Asp113Glu)	CTNNA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1703204	NM_000059.4(BRCA2):c.9981del (p.Lys3327fs)	BRCA2	Uncertain significance	criteria provided, single submitter
1700652	NM_001903.5(CTNNA1):c.1392del (p.Ile465fs)	CTNNA1	Uncertain significance	no assertion criteria provided
1700654	NM_001903.5(CTNNA1):c.1715T>C (p.Val572Ala)	CTNNA1	Uncertain significance	no assertion criteria provided
1700655	NM_001903.5(CTNNA1):c.2665A>G (p.Lys889Glu)	CTNNA1	Uncertain significance	criteria provided, single submitter
1710971	NM_013372.7(GREM1):c.77A>G (p.Lys26Arg)	GREM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1791923	NM_013372.7(GREM1):c.10A>G (p.Thr4Ala)	GREM1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 24 · 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
GREM1	Definitive	Autosomal dominant	hereditary mixed polyposis syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GREM1	Orphanet:157794	Hereditary mixed polyposis syndrome
BRCA1	Orphanet:1331	Familial prostate cancer
BRCA1	Orphanet:1333	Familial pancreatic carcinoma
BRCA1	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA1	Orphanet:168829	Primary peritoneal carcinoma
BRCA1	Orphanet:227535	Hereditary breast cancer
BRCA1	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA1	Orphanet:694963	Inflammatory breast cancer
BRCA1	Orphanet:70567	Cholangiocarcinoma
BRCA1	Orphanet:84	Fanconi anemia
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
CTNNA1	Orphanet:26106	Hereditary diffuse gastric cancer
CTNNA1	Orphanet:99001	Butterfly-shaped pigment dystrophy

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GREM1	HGNC:2001	ENSG00000166923	O60565	Gremlin-1	gencc,clinvar
BRCA1	HGNC:1100	ENSG00000012048	P38398	Breast cancer type 1 susceptibility protein	clinvar
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
CTNNA1	HGNC:2509	ENSG00000044115	P35221	Catenin alpha-1	clinvar
ARHGAP11A-SCG5	HGNC:56310	ENSG00000288864		ARHGAP11A-SCG5 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GREM1	Gremlin-1	Cytokine that may play an important role during carcinogenesis and metanephric kidney organogenesis, as a BMP antagonist required for early limb outgrowth and patterning in maintaining the FGF4-SHH feedback loop.
BRCA1	Breast cancer type 1 susceptibility protein	E3 ubiquitin-protein ligase that specifically mediates the formation of ‘Lys-6’-linked polyubiquitin chains and plays a central role in DNA repair by facilitating cellular responses to DNA damage.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
CTNNA1	Catenin alpha-1	Associates with the cytoplasmic domain of a variety of cadherins.

Protein-family classification

Druggable: 0 · Difficult: 1 · 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
Transcription factor	1	1.6×	0.476
Other/Unknown	4	1.4×	0.476

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GREM1	Other/Unknown	no		DAN_dom, Cys_knot_C, Gremlin-1/2
BRCA1	Transcription factor	no	2.3.2.27	BRCT_dom, Znf_RING, BRCA1
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
CTNNA1	Other/Unknown	no		Vinculin_CS, Alpha_catenin, Vinculin/catenin
ARHGAP11A-SCG5	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

5 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	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
ventricular zone	2
gall bladder	1
mucosa of stomach	1
stromal cell of endometrium	1
primordial germ cell in gonad	1
secondary oocyte	1
amniotic fluid	1
calcaneal tendon	1
colonic epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GREM1	126	ubiquitous	marker	stromal cell of endometrium, gall bladder, mucosa of stomach
BRCA1	208	ubiquitous	marker	ventricular zone, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
CTNNA1	305	ubiquitous	marker	colonic epithelium, calcaneal tendon, amniotic fluid
ARHGAP11A-SCG5			marker

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRCA1	9,064
BRCA2	4,839
CTNNA1	3,128
GREM1	1,180
ARHGAP11A-SCG5	0

Intra-cohort edges

A	B	Sources
BRCA1	BRCA2	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRCA1	P38398	33
BRCA2	P51587	14
CTNNA1	P35221	10
GREM1	O60565	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 74. Enrichment computed across 5 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective homologous recombination repair (HRR) due to PALB2 loss of function	2	475.8×	2e-04	BRCA1, BRCA2
Diseases of DNA Double-Strand Break Repair	2	407.9×	2e-04	BRCA1, BRCA2
Defective homologous recombination repair (HRR) due to BRCA2 loss of function	2	407.9×	2e-04	BRCA1, BRCA2
Resolution of D-Loop Structures	2	317.2×	3e-04	BRCA1, BRCA2
Diseases of DNA repair	2	285.5×	3e-04	BRCA1, BRCA2
Impaired BRCA2 binding to PALB2	2	228.4×	3e-04	BRCA1, BRCA2
Defective homologous recombination repair (HRR) due to BRCA1 loss of function	2	211.5×	3e-04	BRCA1, BRCA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function	2	211.5×	3e-04	BRCA1, BRCA2
Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function	2	211.5×	3e-04	BRCA1, BRCA2
Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)	2	196.9×	3e-04	BRCA1, BRCA2
Homologous DNA Pairing and Strand Exchange	2	190.3×	3e-04	BRCA1, BRCA2
Homology Directed Repair	2	154.3×	3e-04	BRCA1, BRCA2
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	2	154.3×	3e-04	BRCA1, BRCA2
Impaired BRCA2 binding to RAD51	2	154.3×	3e-04	BRCA1, BRCA2
Resolution of D-loop Structures through Holliday Junction Intermediates	2	150.3×	3e-04	BRCA1, BRCA2
Meiosis	2	142.8×	3e-04	BRCA1, BRCA2
Presynaptic phase of homologous DNA pairing and strand exchange	2	135.9×	3e-04	BRCA1, BRCA2
DNA Double-Strand Break Repair	2	124.1×	4e-04	BRCA1, BRCA2
Reproduction	2	95.2×	6e-04	BRCA1, BRCA2
HDR through Homologous Recombination (HRR)	2	95.2×	6e-04	BRCA1, BRCA2
Meiotic recombination	2	64.9×	0.001	BRCA1, BRCA2
DNA Repair	2	49.2×	0.002	BRCA1, BRCA2
Defective DNA double strand break response due to BRCA1 loss of function	1	1427.5×	0.002	BRCA1
Defective DNA double strand break response due to BARD1 loss of function	1	1427.5×	0.002	BRCA1
Impaired BRCA2 translocation to the nucleus	1	951.7×	0.003	BRCA2
Impaired BRCA2 binding to SEM1 (DSS1)	1	951.7×	0.003	BRCA2
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	1	407.9×	0.006	BRCA1
CDH11 homotypic and heterotypic interactions	1	407.9×	0.006	CTNNA1
Regulation of CDH19 Expression and Function	1	356.9×	0.007	CTNNA1
Regulation of CDH11 function	1	259.6×	0.009	CTNNA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular response to indole-3-methanol	2	1685.2×	5e-05	BRCA1, CTNNA1
regulation of DNA damage checkpoint	2	561.7×	3e-04	BRCA1, BRCA2
cellular response to ionizing radiation	2	205.5×	0.001	BRCA1, BRCA2
double-strand break repair	2	101.5×	0.004	BRCA1, BRCA2
double-strand break repair via homologous recombination	2	78.0×	0.006	BRCA1, BRCA2
negative regulation of bone remodeling	1	2106.5×	0.006	GREM1
negative regulation of bone trabecula formation	1	2106.5×	0.006	GREM1
mitotic recombination-dependent replication fork processing	1	2106.5×	0.006	BRCA2
positive regulation of angiogenesis	2	57.7×	0.006	GREM1, BRCA1
obsolete sequestering of BMP from receptor via BMP binding	1	1404.3×	0.008	GREM1
negative regulation of osteoclast proliferation	1	1404.3×	0.008	GREM1
negative regulation of bone mineralization involved in bone maturation	1	1053.2×	0.009	GREM1
negative regulation of integrin-mediated signaling pathway	1	1053.2×	0.009	CTNNA1
negative regulation of mammary gland epithelial cell proliferation	1	842.6×	0.010	BRCA2
determination of dorsal identity	1	842.6×	0.010	GREM1
chordate embryonic development	1	702.2×	0.010	BRCA1
negative regulation of monocyte chemotaxis	1	702.2×	0.010	GREM1
negative regulation of centriole replication	1	601.9×	0.010	BRCA1
ureteric bud formation	1	601.9×	0.010	GREM1
mesenchymal to epithelial transition involved in metanephros morphogenesis	1	526.6×	0.010	GREM1
gap junction assembly	1	526.6×	0.010	CTNNA1
apical junction assembly	1	526.6×	0.010	CTNNA1
establishment of protein localization to telomere	1	526.6×	0.010	BRCA2
DNA strand resection involved in replication fork processing	1	526.6×	0.010	BRCA1
DNA damage tolerance	1	421.3×	0.011	BRCA1
response to UV-C	1	421.3×	0.011	BRCA2
telomere maintenance via recombination	1	383.0×	0.011	BRCA2
regulation of epithelial to mesenchymal transition	1	383.0×	0.011	GREM1
negative regulation of osteoblast proliferation	1	383.0×	0.011	GREM1
positive regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	383.0×	0.011	CTNNA1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) 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
BRCA1	RIBOFLAVIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRCA1	12	4
GREM1	0	0
BRCA2	0	0
CTNNA1	0	0
ARHGAP11A-SCG5	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	BRCA1
CURCUMIN	3	BRCA1
SURAMIN	3	BRCA1
SURAMIN HEXASODIUM	3	BRCA1
SODIUM TANSHINONE IIA SULFONATE	2	BRCA1
HOMIDIUM BROMIDE	2	BRCA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BRCA1	13	Binding:9, Functional:4
CTNNA1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRCA1	2.3.2.27	RING-type E3 ubiquitin transferase

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).

Chemical tractability of cohort targets

12 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.

Compound	Max phase	Cohort target (bioactivity)
RIBOFLAVIN	4	BRCA1
DAUNORUBICIN HYDROCHLORIDE	4	BRCA1
TOPOTECAN HYDROCHLORIDE	4	BRCA1
DAUNORUBICIN	4	BRCA1
DOXORUBICIN HYDROCHLORIDE	4	BRCA1
MESALAMINE	4	BRCA1
DIPYRIDAMOLE	4	BRCA1
CURCUMIN	3	BRCA1
SURAMIN	3	BRCA1
SURAMIN HEXASODIUM	3	BRCA1
SODIUM TANSHINONE IIA SULFONATE	2	BRCA1
HOMIDIUM BROMIDE	2	BRCA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRCA1
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	4	GREM1, BRCA2, CTNNA1, ARHGAP11A-SCG5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BRCA2	0	BRCA1
GREM1	0	—
CTNNA1	2	—
ARHGAP11A-SCG5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06447961	Not specified	RECRUITING	PSYLIVED: the Psychological Impacts of Living With an Inherited Colorectal Cancer Predisposition Syndrome