POLE
DNA polymerase epsilon, catalytic subunit, the group of DNA polymerases
Basic information
Region (hg38): 12:132623753-132687376
Links
Phenotypes
GenCC
Source:
- colorectal cancer, susceptibility to, 12 (Strong), mode of inheritance: AD
- colorectal cancer, susceptibility to, 12 (Strong), 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
- intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency (Strong), mode of inheritance: AR
Clinical Genomic Database
Source:
| 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
- not_provided (8563 variants)
- Hereditary_cancer-predisposing_syndrome (5416 variants)
- Colorectal_cancer,_susceptibility_to,_12 (1030 variants)
- not_specified (995 variants)
- Facial_dysmorphism-immunodeficiency-livedo-short_stature_syndrome (386 variants)
- Intrauterine_growth_retardation,_metaphyseal_dysplasia,_adrenal_hypoplasia_congenita,_genital_anomalies,_and_immunodeficiency (325 variants)
- POLE-related_disorder (276 variants)
- Polymerase_proofreading-related_adenomatous_polyposis (149 variants)
- Familial_colorectal_cancer_type_X (103 variants)
- Familial_colorectal_cancer (40 variants)
- Carcinoma_of_colon (35 variants)
- POLE-related_polyposis_and_colorectal_cancer_syndrome (26 variants)
- Colorectal_cancer,_susceptibility_to,_10 (20 variants)
- Hereditary_cancer (19 variants)
- Malignant_tumor_of_breast (11 variants)
- Colorectal_cancer (10 variants)
- Diffuse_midline_glioma,_H3_K27-altered (3 variants)
- Polymerase_proofreading_associated_polyposis (2 variants)
- Familial_ovarian_cancer (2 variants)
- Pediatric_high-grade_glioma (2 variants)
- Programmed_death_ligand-1_(PD-L1)_blocking_antibody_response (2 variants)
- Endometrioid_adenocarcinoma (1 variants)
- POLE_Exonuclease_Domain_Mutation (1 variants)
- Intestinal_polyposis_syndrome (1 variants)
- Cancer_or_benign_tumor (1 variants)
- Inherited_polyposis_and_early_onset_colorectal_cancer_-_germline_testing (1 variants)
- Myoepithelial_tumor (1 variants)
- Cystic_fibrosis-gastritis-megaloblastic_anemia_syndrome (1 variants)
- Endometrial_carcinoma (1 variants)
- Neuroepithelial_neoplasm (1 variants)
- Colorectal_carcinoma (1 variants)
- Colorectal_cancer_susceptibility_12 (1 variants)
- Colon_cancer (1 variants)
- XFE_progeroid_syndrome (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. These statistics are base on transcript: NM_000006231.4. Only rare variants are included in the table.
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.
| Effect | PathogenicP | Likely pathogenicLP | VUSVUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 66 | 2192 | 28 | 2288 | ||
| missense | 19 | 4652 | 422 | 5107 | ||
| nonsense | 89 | 75 | 26 | 190 | ||
| start loss | 1 | 5 | 4 | 10 | ||
| frameshift | 240 | 104 | 86 | 432 | ||
| splice donor/acceptor (+/-2bp) | 153 | 43 | 204 | |||
| Total | 344 | 358 | 4877 | 2618 | 34 |
Highest pathogenic variant AF is 0.0000818118
Loading clinvar variants...
GnomAD
Source:
| 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:
- 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