POLE-related polyposis and colorectal cancer syndrome

Summary

POLE-related polyposis and colorectal cancer syndrome (MONDO:0100287) is a cancer caused by POLE (GenCC Definitive), with 1 cohort gene (1 CIViC-evidence somatic driver; 34 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: POLE (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 34

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	POLE-related polyposis and colorectal cancer syndrome
Mondo ID	MONDO:0100287
GARD	0026124
Is cancer (heuristic)	yes

Data availability: 34 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › cancer or benign tumor › polyp › neoplastic polyp › polyposis › POLE-related polyposis and colorectal cancer syndrome

Related subtypes (3): polyposis, intestinal, scattered and discrete, gastric adenocarcinoma and proximal polyposis of the stomach, POLD1-related polyposis and colorectal cancer syndrome

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

34 retrieved; paginated sample, class counts are floors:

17 likely benign, 6 benign/likely benign, 5 conflicting classifications of pathogenicity, 4 benign, 1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
619085	NM_006231.4(POLE):c.1686+32C>G	POLE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1134372	NM_006231.4(POLE):c.3379-4G>A	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240412	NM_006231.4(POLE):c.1924-5C>T	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
240463	NM_006231.4(POLE):c.330+3G>A	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
381760	NM_006231.4(POLE):c.1360-14C>T	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
405829	NM_006231.4(POLE):c.5173+1G>T	POLE	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
405791	NM_006231.4(POLE):c.2209A>G (p.Thr737Ala)	POLE	Uncertain significance	criteria provided, multiple submitters, no conflicts
1559688	NM_006231.4(POLE):c.62+13C>T	LOC130009266	Likely benign	criteria provided, multiple submitters, no conflicts
380208	NM_006231.4(POLE):c.62+15C>T	LOC130009266	Benign	criteria provided, multiple submitters, no conflicts
1143272	NM_006231.4(POLE):c.801+8T>A	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
1151808	NM_006231.4(POLE):c.5552+10C>A	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
1595964	NM_006231.4(POLE):c.5552+13C>T	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
221145	NM_006231.4(POLE):c.1359+9G>A	POLE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
3677452	NM_006231.4(POLE):c.330+15T>C	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
371924	NM_006231.4(POLE):c.1226+13G>A	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
371925	NM_006231.4(POLE):c.4952+11T>A	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
3780465	NM_006231.4(POLE):c.2026+9C>G	POLE	Likely benign	criteria provided, single submitter
380209	NM_006231.4(POLE):c.910-6G>C	POLE	Benign	criteria provided, multiple submitters, no conflicts
380213	NM_006231.4(POLE):c.4444+4T>A	POLE	Benign	criteria provided, multiple submitters, no conflicts
380218	NM_006231.4(POLE):c.6330+15G>A	POLE	Benign	criteria provided, multiple submitters, no conflicts
380709	NM_006231.4(POLE):c.4552-11C>T	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
381931	NM_006231.4(POLE):c.6532-11G>C	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
385730	NM_006231.4(POLE):c.6748-11T>A	POLE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
386531	NM_006231.4(POLE):c.1360-13G>A	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
386826	NM_006231.4(POLE):c.285+13C>A	POLE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
391845	NM_006231.4(POLE):c.4952+10G>A	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
413539	NM_006231.4(POLE):c.1924-6T>C	POLE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
413555	NM_006231.4(POLE):c.721-4G>T	POLE	Likely benign	criteria provided, multiple submitters, no conflicts
439266	NM_006231.4(POLE):c.2865-4dup	POLE	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
473650	NM_006231.4(POLE):c.4150-8C>A	POLE	Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
POLE	Act	ACC,BLCA	CIViC #4386

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
POLE	Definitive	Autosomal dominant	POLE-related polyposis and colorectal cancer syndrome	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLE	Orphanet:352712	Facial dysmorphism-immunodeficiency-livedo-short stature syndrome
POLE	Orphanet:440437	Familial colorectal cancer Type X
POLE	Orphanet:447877	Polymerase proofreading-related polyposis
POLE	Orphanet:85173	IMAGe 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
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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	8.3×	0.121

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLE	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B, RNaseH-like_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
cerebellar hemisphere	1
right hemisphere of cerebellum	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLE	3,267

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLE	Q07864	18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
DNA replication initiation	1	1427.5×	0.005	POLE
PCNA-Dependent Long Patch Base Excision Repair	1	519.1×	0.005	POLE
Gap-filling DNA repair synthesis and ligation in GG-NER	1	439.2×	0.005	POLE
Recognition of DNA damage by PCNA-containing replication complex	1	380.7×	0.005	POLE
Termination of translesion DNA synthesis	1	346.1×	0.005	POLE
Activation of the pre-replicative complex	1	326.3×	0.005	POLE
Dual Incision in GG-NER	1	259.6×	0.006	POLE
HDR through Homologous Recombination (HRR)	1	190.3×	0.006	POLE
Gap-filling DNA repair synthesis and ligation in TC-NER	1	178.4×	0.006	POLE
Dual incision in TC-NER	1	173.0×	0.006	POLE

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
DNA replication proofreading	1	5617.3×	0.001	POLE
leading strand elongation	1	4213.0×	0.001	POLE
nucleotide-excision repair, DNA gap filling	1	2808.7×	0.001	POLE
base-excision repair, gap-filling	1	1123.5×	0.002	POLE
DNA synthesis involved in DNA repair	1	936.2×	0.002	POLE
DNA-templated DNA replication	1	561.7×	0.003	POLE
embryonic organ development	1	481.5×	0.003	POLE
G1/S transition of mitotic cell cycle	1	200.6×	0.006	POLE
DNA replication	1	165.2×	0.007	POLE
mitotic cell cycle	1	133.8×	0.007	POLE

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
POLE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLE	2.7.7.7	DNA-directed DNA polymerase

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	POLE

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)
POLE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.