POLE

DNA polymerase epsilon, catalytic subunit, the group of DNA polymerases

Basic information

Region (hg38): 12:132623752-132687376

Links

ENSG00000177084 ∙ NCBI:5426 ∙ OMIM:174762 ∙ HGNC:9177 ∙ Uniprot:Q07864 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• colorectal cancer, susceptibility to, 12 (Strong), mode of inheritance: AD
• colorectal cancer, susceptibility to, 12 (Moderate), mode of inheritance: AD
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Moderate), mode of inheritance: AR
• IMAGe syndrome (Supportive), mode of inheritance: AD
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Supportive), mode of inheritance: AR
• Polymerase proofreading-related adenomatous polyposis (Supportive), mode of inheritance: AD
• facial dysmorphism-immunodeficiency-livedo-short stature syndrome (Strong), mode of inheritance: AR
• colorectal cancer, susceptibility to, 12 (Strong), mode of inheritance: AD
• POLE-related polyposis and colorectal cancer syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Colorectal cancer, susceptibility to, 12; Facial dysmorphism, immunodeficiency, livedo, and short stature syndrome (FILS syndrome); Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (IMAGEI)	AD/AR	Allergy/Immunology/Infectious; Endocrine; Oncologic	In Colorectal cancer, susceptibility to, described individuals manifest edwith colorectal adenomas, with a high risk of colorectal carcinoma, and screening (eg, with colonoscopy) may allow early detection and treatment, potentially ameliorating morbidity and mortality; Other neoplasms have been described in affected individuals, and knowledge of the increased risk may allow early detection and treatment; In FILS syndrome and IMAGEI, individuals may have immunodeficiency, and prophylactic measures and awareness of the risk of infections may allow early and aggressive treatment of infectious manifestations; In IMAGEI, the condition may include adrenal insufficiency, and awareness may allow medical management of the condition	Allergy/Immunology/Infectious; Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Oncologic	14760276; 16835919; 23230001; 23263490; 24501277; 25370038; 30503519
In Colorectal cancer, susceptibility to, individuals have been described such that the presence of variants would warrant surveillance in the pediatric period

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the POLE gene.

• Colorectal cancer, susceptibility to, 12 (5167 variants)
• Hereditary cancer-predisposing syndrome (3249 variants)
• not provided (3107 variants)
• not specified (903 variants)
• POLE-related condition (50 variants)
• Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (41 variants)
• Carcinoma of colon (37 variants)
• Familial colorectal cancer (37 variants)
• Colorectal cancer, susceptibility to, 12;Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (27 variants)
• Colorectal cancer, susceptibility to, 12;Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (27 variants)
• Inborn genetic diseases (26 variants)
• Polymerase proofreading-related adenomatous polyposis (25 variants)
• Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (25 variants)
• Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency;Colorectal cancer, susceptibility to, 12;Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (20 variants)
• Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;Colorectal cancer, susceptibility to, 12 (19 variants)
• Hereditary cancer (16 variants)
• Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency;Colorectal cancer, susceptibility to, 12 (15 variants)
• Malignant tumor of breast (11 variants)
• Colorectal cancer (9 variants)
• Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;Colorectal cancer, susceptibility to, 12;Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (7 variants)
• Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;Familial colorectal cancer (6 variants)
• Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency;Facial dysmorphism-immunodeficiency-livedo-short stature syndrome;Colorectal cancer, susceptibility to, 12 (6 variants)
• Familial colorectal cancer;Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (5 variants)
• Malignant neoplasm of body of uterus (2 variants)
• Neoplasm of the large intestine (2 variants)
• Colorectal cancer, susceptibility to, 12;Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency;Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (2 variants)
• - (2 variants)
• Colorectal cancer susceptibility 12 (1 variants)
• Endometrioid adenocarcinoma (1 variants)
• Glioblastoma (1 variants)
• Short stature (1 variants)
• Familial ovarian cancer (1 variants)
• Endometrial carcinoma (1 variants)
• Colon cancer (1 variants)
• Programmed death ligand-1 (PD-L1) blocking antibody response (1 variants)
• Pancreatic adenocarcinoma (1 variants)
• Diffuse midline glioma, H3 K27-altered (1 variants)
• Cystic fibrosis-gastritis-megaloblastic anemia syndrome (1 variants)
• Polymerase proofreading associated polyposis (1 variants)
• Gastric adenocarcinoma (1 variants)
• POLE-related disorders (1 variants)
• Uterine carcinosarcoma (1 variants)
• Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency;Facial dysmorphism-immunodeficiency-livedo-short stature syndrome (1 variants)
• POLE Exonuclease Domain Mutation (1 variants)
• Breast neoplasm (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the POLE gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			28	1787	9	1824
missense	1	3	3887	24	6	3921
nonsense	83	4	21			108
start loss			2			2
frameshift	187	2	51			240
inframe indel			78			78
splice donor/acceptor (+/-2bp)	1	82	25			108
splice region	1	9	225	287	5	527
non coding	1	3	49	1018	95	1166
Total	273	94	4141	2829	110

Highest pathogenic variant AF is 0.00000659

Variants in POLE

This is a list of pathogenic ClinVar variants found in the POLE region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-132624607-T-C			Benign (Jun 18, 2018)
12-132624670-G-A		not specified	Likely benign (Feb 06, 2024)
12-132624674-A-C		not specified	Likely benign (Aug 15, 2023)
12-132624679-C-A		not specified • Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (Aug 15, 2023)
12-132624681-C-T			Likely benign (Nov 15, 2017)
12-132624693-C-A		Hereditary cancer-predisposing syndrome	Uncertain significance (May 18, 2016)
12-132624700-A-G			Likely benign (Feb 21, 2021)
12-132624701-T-C		Hereditary cancer-predisposing syndrome	Likely benign (Jul 04, 2023)
12-132624704-C-G		Hereditary cancer-predisposing syndrome	Uncertain significance (Jul 18, 2021)
12-132624704-C-T			Uncertain significance (Nov 03, 2023)
12-132624705-C-A		Hereditary cancer-predisposing syndrome	Uncertain significance (May 25, 2023)
12-132624705-C-T			Uncertain significance (Nov 11, 2023)
12-132624706-C-T		Hereditary cancer-predisposing syndrome	Likely benign (Mar 23, 2023)
12-132624707-A-T			Uncertain significance (Nov 21, 2019)
12-132624708-G-A		Hereditary cancer-predisposing syndrome	Likely benign (Aug 03, 2019)
12-132624708-G-T			Uncertain significance (May 28, 2023)
12-132624709-C-A			Uncertain significance (Jul 23, 2019)
12-132624709-C-T			Likely benign (Jan 04, 2024)
12-132624711-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Oct 24, 2022)
12-132624711-G-C			Uncertain significance (Dec 14, 2023)
12-132624712-T-C			Likely benign (Jul 25, 2022)
12-132624712-T-G		Hereditary cancer-predisposing syndrome	Likely benign (Jul 10, 2023)
12-132624713-G-A		Hereditary cancer-predisposing syndrome	Uncertain significance (Aug 29, 2023)
12-132624713-G-C		Hereditary cancer-predisposing syndrome	Uncertain significance (Aug 09, 2023)
12-132624714-G-A			Uncertain significance (Oct 14, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
POLE	protein_coding	protein_coding	ENST00000320574	49	63604

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
8.05e-27	1.00	125571	0	177	125748	0.000704

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.07	1287	1.40e+3	0.920	0.0000912	15040
Missense in Polyphen		390	529.32	0.7368		5610
Synonymous	-1.01	596	566	1.05	0.0000394	4374
Loss of Function	4.94	64	123	0.520	0.00000632	1370

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00173	0.00173
Ashkenazi Jewish	0.000198	0.000198
East Asian	0.000819	0.000816
Finnish	0.000232	0.000231
European (Non-Finnish)	0.000778	0.000765
Middle Eastern	0.000819	0.000816
South Asian	0.000653	0.000653
Other	0.000654	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Participates in DNA repair and in chromosomal DNA replication.
• Disease: DISEASE: Colorectal cancer 12 (CRCS12) [MIM:615083]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. CRCS12 is characterized by a high-penetrance predisposition to the development of colorectal adenomas and carcinomas, with a variable tendency to develop multiple and large tumors. Onset is usually before age 40 years. The histologic features of the tumors are unremarkable. {ECO:0000269|PubMed:23263490, ECO:0000269|PubMed:24501277, ECO:0000269|PubMed:25860647, ECO:0000269|PubMed:27573199}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) [MIM:615139]: A syndrome characterized by mild facial dysmorphism, mainly malar hypoplasia, livedo on the skin since birth, and immunodeficiency resulting in recurrent infections. Growth impairment is observed during early childhood and results in variable short stature in adulthood. {ECO:0000269|PubMed:23230001}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Nucleotide excision repair - Homo sapiens (human);Pyrimidine metabolism - Homo sapiens (human);Base excision repair - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);DNA replication - Homo sapiens (human);Purine metabolism - Homo sapiens (human);Nucleotide Excision Repair ;Retinoblastoma (RB) in Cancer;Pyrimidine metabolism;G1 to S cell cycle control;DNA Replication;HDR through Homologous Recombination (HR) or Single Strand Annealing (SSA);DNA Repair;DNA Double-Strand Break Repair;Homology Directed Repair;Purine metabolism;Activation of the pre-replicative complex;Mitotic G1-G1/S phases;DNA replication initiation;DNA Replication;Pyrimidine metabolism;Synthesis of DNA;S Phase;PCNA-Dependent Long Patch Base Excision Repair;Resolution of AP sites via the multiple-nucleotide patch replacement pathway;Resolution of Abasic Sites (AP sites);Base Excision Repair;Telomere C-strand synthesis initiation;Telomere C-strand (Lagging Strand) Synthesis;Extension of Telomeres;Telomere Maintenance;Chromosome Maintenance;G1/S Transition;Recognition of DNA damage by PCNA-containing replication complex;DNA Replication Pre-Initiation;M/G1 Transition;Termination of translesion DNA synthesis;Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template;DNA Damage Bypass;Cell Cycle;Dual Incision in GG-NER;Gap-filling DNA repair synthesis and ligation in GG-NER;Global Genome Nucleotide Excision Repair (GG-NER);Cell Cycle, Mitotic;Dual incision in TC-NER;Gap-filling DNA repair synthesis and ligation in TC-NER;Transcription-Coupled Nucleotide Excision Repair (TC-NER);Nucleotide Excision Repair;HDR through Homologous Recombination (HRR) (Consensus)

Intolerance Scores

• loftool: 0.864
• rvis_EVS: -0.81
• rvis_percentile_EVS: 12.09

Haploinsufficiency Scores

• pHI: 0.600
• hipred: Y
• hipred_score: 0.747
• ghis: 0.541

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.997

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Pole
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); immune system phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype

Gene ontology

• Biological process: G1/S transition of mitotic cell cycle;mitotic cell cycle;DNA synthesis involved in DNA repair;DNA replication;leading strand elongation;base-excision repair, gap-filling;nucleotide-excision repair, DNA gap filling;DNA replication proofreading;embryonic organ development;nucleic acid phosphodiester bond hydrolysis
• Cellular component: nucleus;nucleoplasm;plasma membrane;epsilon DNA polymerase complex
• Molecular function: nucleotide binding;DNA binding;chromatin binding;DNA-directed DNA polymerase activity;protein binding;zinc ion binding;single-stranded DNA 3'-5' exodeoxyribonuclease activity;4 iron, 4 sulfur cluster binding