Colorectal cancer, susceptibility to, 10

Summary

Colorectal cancer, susceptibility to, 10 (MONDO:0012953) is a cancer caused by POLD1 (GenCC Strong), with 3 cohort genes (2 CIViC-evidence somatic drivers; 4,785 ClinVar predisposition records).

At a glance

• Classification: Cancer
• Causal gene: POLD1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 4,785

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	colorectal cancer, susceptibility to, 10
Mondo ID	MONDO:0012953
OMIM	612591
UMLS	C2675481
MedGen	436445
GARD	0027828
Is cancer (heuristic)	yes

Also known as: colorectal cancer caused by mutation in POLD1 · colorectal cancer, susceptibility to, 10 · colorectal cancer, susceptibility to, type 10 · CRCS10 · POLD1 colorectal cancer

Data availability: 4,785 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 › colorectal cancer, susceptibility to, 10

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, 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

600 retrieved; paginated sample, class counts are floors:

355 uncertain significance, 187 likely benign, 33 conflicting classifications of pathogenicity, 23 benign/likely benign, 1 benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
144003	NM_002691.4(POLD1):c.1421T>C (p.Leu474Pro)	POLD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1002952	NM_002691.4(POLD1):c.921T>G (p.Ile307Met)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1007689	NM_002691.4(POLD1):c.123G>T (p.Met41Ile)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1023429	NM_002691.4(POLD1):c.863C>T (p.Ala288Val)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1042209	NM_002691.4(POLD1):c.740A>G (p.Asn247Ser)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1044169	NM_002691.4(POLD1):c.2940G>T (p.Glu980Asp)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1051713	NM_002691.4(POLD1):c.1721A>G (p.Lys574Arg)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1058535	NM_002691.4(POLD1):c.703G>A (p.Gly235Ser)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064020	NM_002691.4(POLD1):c.2965A>G (p.Thr989Ala)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1089173	NM_002691.4(POLD1):c.172C>T (p.Leu58=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1095719	NM_002691.4(POLD1):c.1383+4del	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1096791	NM_002691.4(POLD1):c.1495-4C>T	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1102497	NM_002691.4(POLD1):c.2565-7C>T	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1106105	NM_002691.4(POLD1):c.2793G>A (p.Lys931=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1109586	NM_002691.4(POLD1):c.3009G>T (p.Leu1003=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1126226	NM_002691.4(POLD1):c.1305A>C (p.Ser435=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1144381	NM_002691.4(POLD1):c.1470G>A (p.Gln490=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1146160	NM_002691.4(POLD1):c.2106C>A (p.Gly702=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1149965	NM_002691.4(POLD1):c.2850G>A (p.Leu950=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1153982	NM_002691.4(POLD1):c.1494+10G>A	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1190288	NM_002691.4(POLD1):c.1582G>A (p.Val528Met)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1196332	NM_002691.4(POLD1):c.3219-11C>G	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1305724	NM_002691.4(POLD1):c.80A>G (p.Asp27Gly)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1306277	NM_002691.4(POLD1):c.1138-11C>A	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1308212	NM_002691.4(POLD1):c.3121-12T>C	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1308839	NM_002691.4(POLD1):c.614G>A (p.Gly205Asp)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1312099	NM_002691.4(POLD1):c.417C>T (p.Cys139=)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1313787	NM_002691.4(POLD1):c.3068-5C>A	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1319263	NM_002691.4(POLD1):c.2717+12_2717+13del	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1399914	NM_002691.4(POLD1):c.365T>C (p.Val122Ala)	POLD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Somatic driver evidence (intOGen + CIViC, cohort fanout)

Gene	intOGen role	Cancer types	CIViC
POLD1	LoF	BRCA,ESCA	CIViC #4384
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
POLD1	Definitive	Autosomal dominant	POLD1-related polyposis and colorectal cancer syndrome	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POLD1	Orphanet:363649	Mandibular hypoplasia-deafness-progeroid features-lipodystrophy syndrome
POLD1	Orphanet:440437	Familial colorectal cancer Type X
POLD1	Orphanet:447877	Polymerase proofreading-related polyposis
KCNC3	Orphanet:98768	Spinocerebellar ataxia type 13
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

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POLD1	HGNC:9175	ENSG00000062822	P28340	DNA polymerase delta catalytic subunit	gencc,clinvar
KCNC3	HGNC:6235	ENSG00000131398	Q14003	Voltage-gated potassium channel KCNC3	clinvar
POLE	HGNC:9177	ENSG00000177084	Q07864	DNA polymerase epsilon catalytic subunit A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POLD1	DNA polymerase delta catalytic subunit	As the catalytic component of the trimeric (Pol-delta3 complex) and tetrameric DNA polymerase delta complexes (Pol-delta4 complex), plays a crucial role in high fidelity genome replication, including in lagging strand synthesis, and repair.
KCNC3	Voltage-gated potassium channel KCNC3	Voltage-gated potassium channel that plays an important role in the rapid repolarization of fast-firing brain neurons.
POLE	DNA polymerase epsilon catalytic subunit A	Catalytic component of the DNA polymerase epsilon complex.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 0 · Druggable fraction: 0.33

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
Ion channel	1	37.2×	0.040
Transcription factor	2	5.5×	0.040

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POLD1	Transcription factor	no	2.7.7.7	DNA-dir_DNA_pol_B_exonuc, DNA-dir_DNA_pol_B_multi_dom, DNA-dir_DNA_pol_B
KCNC3	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
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.

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	1
primordial germ cell in gonad	1
ventricular zone	1
cerebellar vermis	1
kidney epithelium	1
right uterine tube	1
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
POLD1	134	ubiquitous	marker	mucosa of transverse colon, ventricular zone, primordial germ cell in gonad
KCNC3	192	ubiquitous	yes	kidney epithelium, right uterine tube, cerebellar vermis
POLE	221	ubiquitous	marker	right hemisphere of cerebellum, right testis, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POLD1	4,000
POLE	3,267
KCNC3	2,099

Intra-cohort edges

A	B	Sources
POLD1	POLE	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
POLE	Q07864	18
POLD1	P28340	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNC3	Q14003	66.01

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 23. Enrichment computed across 3 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
PCNA-Dependent Long Patch Base Excision Repair	2	346.1×	1e-04	POLD1, POLE
Gap-filling DNA repair synthesis and ligation in GG-NER	2	292.8×	1e-04	POLD1, POLE
Recognition of DNA damage by PCNA-containing replication complex	2	253.8×	1e-04	POLD1, POLE
Termination of translesion DNA synthesis	2	230.7×	1e-04	POLD1, POLE
Dual Incision in GG-NER	2	173.0×	2e-04	POLD1, POLE
HDR through Homologous Recombination (HRR)	2	126.9×	3e-04	POLD1, POLE
Gap-filling DNA repair synthesis and ligation in TC-NER	2	119.0×	3e-04	POLD1, POLE
Dual incision in TC-NER	2	115.3×	3e-04	POLD1, POLE
DNA replication initiation	1	475.8×	0.005	POLE
Processive synthesis on the lagging strand	1	380.7×	0.005	POLD1
Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)	1	271.9×	0.005	POLD1
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	271.9×	0.005	POLD1
Polymerase switching	1	271.9×	0.005	POLD1
Removal of the Flap Intermediate	1	271.9×	0.005	POLD1
Processive synthesis on the C-strand of the telomere	1	253.8×	0.005	POLD1
Telomere C-strand (Lagging Strand) Synthesis	1	253.8×	0.005	POLD1
Cytosolic iron-sulfur cluster assembly	1	253.8×	0.005	POLD1
Removal of the Flap Intermediate from the C-strand	1	211.5×	0.006	POLD1
Polymerase switching on the C-strand of the telomere	1	141.0×	0.009	POLD1
Activation of the pre-replicative complex	1	108.8×	0.011	POLE
Voltage gated Potassium channels	1	81.0×	0.013	KCNC3
Potassium Channels	1	44.8×	0.023	KCNC3
Neuronal System	1	14.8×	0.066	KCNC3

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
DNA replication proofreading	2	3744.9×	1e-06	POLD1, POLE
nucleotide-excision repair, DNA gap filling	2	1872.4×	3e-06	POLD1, POLE
base-excision repair, gap-filling	2	749.0×	2e-05	POLD1, POLE
DNA synthesis involved in DNA repair	2	624.1×	2e-05	POLD1, POLE
DNA-templated DNA replication	2	374.5×	4e-05	POLD1, POLE
DNA replication	2	110.1×	4e-04	POLD1, POLE
leading strand elongation	1	1404.3×	0.002	POLE
error-free translesion synthesis	1	1123.5×	0.002	POLD1
fatty acid homeostasis	1	312.1×	0.008	POLD1
DNA biosynthetic process	1	267.5×	0.008	POLD1
protein tetramerization	1	208.1×	0.009	KCNC3
cortical actin cytoskeleton organization	1	200.6×	0.009	KCNC3
embryonic organ development	1	160.5×	0.011	POLE
response to UV	1	122.1×	0.012	POLD1
action potential	1	119.5×	0.012	KCNC3
cellular response to UV	1	98.5×	0.014	POLD1
G1/S transition of mitotic cell cycle	1	66.9×	0.019	POLE
potassium ion transport	1	63.8×	0.019	KCNC3
potassium ion transmembrane transport	1	45.3×	0.024	KCNC3
mitotic cell cycle	1	44.6×	0.024	POLE
protein homooligomerization	1	40.7×	0.026	KCNC3
DNA repair	1	21.3×	0.046	POLD1

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 3 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
POLD1	0	0
KCNC3	0	0
POLE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
KCNC3	21	Binding:20, Toxicity:1
POLD1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POLD1	2.7.7.7	DNA-directed DNA polymerase
POLE	2.7.7.7	DNA-directed DNA polymerase

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

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	1	KCNC3
E	Difficult family or no structure, no drug	2	POLD1, POLE

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)
POLD1	8	—
KCNC3	21	—
POLE	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.