POLE

protein-coding

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

Gene summary

This gene encodes the catalytic subunit of DNA polymerase epsilon. The enzyme is involved in DNA repair and chromosomal DNA replication. Mutations in this gene have been associated with colorectal cancer 12 and facial dysmorphism, immunodeficiency, livedo, and short stature. [provided by RefSeq, Sep 2013]

MANE transcript

NM_006231.4

Inheritance

AR, AD

ClinVar variants

P:739U:5266B:2865

Top phenotype

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)

gnomAD constraint

pLI —, LoF o/e 0.52

Max pathogenic AF

—

Genomic locus

chr12:132,623,753-132,687,376

External References & Databases

Ensembl (ENSG00000177084)

Transcript & Mutation Effects

hg38 • Region Span ~63.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

facial dysmorphism-immunodeficiency-livedo-short stature syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014058

Submitter: Labcorp Genetics (formerly Invitae)

POLE-related polyposis and colorectal cancer syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100287

Submitter: ClinGen

The *POLE* gene encodes the catalytic subunit of DNA polymerase epsilon, which is involved in DNA repair and possibly also in replication of chromosomal DNA. POLE was first reported as an autosomal dominant cancer susceptibility condition in 2013 (Palles et al, PMID: 23263490). Likely pathogenic/pathogenic variants located with the exonuclease domain of POLE are associated with an increased risk of colon polyps and colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s), inheritance pattern and phenotypic variability between cancer susceptibility to colon cancer and colon polyps. Therefore, the following disease entities have been lumped into POLE-related polyposis and colorectal cancer syndrome (MONDO:0100287). However, due to the phenotypic variability, variant type and different inheritance pattern, autosomal recessive Facial Dysmorphism, Immunodeficiency, Livedo, and Short Stature (FILS) syndrome and Intrauterine Growth Retardation, Metaphyseal Dysplasia, Adrenal Hypoplasia, Congenita, Genetial Anomalies, and Immunodeficiency (IMAGE-I) syndrome have been split from this curation. Two missense and one truncated variants that have been reported in seven publications (PMIDs: 25370038, 32792570, 26133394, 24501277, 23263490, 25529843, 34761457) are included in this curation. The variant segregates with disease for each family described. Probands had colon cancer and/or history of multiple colon polyps and were negative for pathogenic variants in the APC and MUTYH genes. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is due to mutations that occur within the exonuclease domain of the POLE gene, which results in a decrease in DNA replication fidelity. This gene-disease association is also supported by experimental evidence (1.75 points) including mouse and yeast models (PMIDs: 19805137, 16699561). These studies demonstrated that mutations in the exonuclease domain of POLE lead to the underlying mechanism of pathogenicity. In summary, POLE is definitively associated with autosomal dominant POLE-related polyposis and colorectal cancer syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This gene-disease pair was originally evaluated by the Colon Cancer Expert Panel on 12/11/2017. The ClinGen Hereditary Cancer GCEP reevaluated on 01/27/2023 (SOP Version 9). As a result of this reevaluation, the classification did not change although the disease name was changed to mirror both features of the disorder.

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032684

Submitter: G2P

colorectal cancer, susceptibility to, 12STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014038

Submitter: Ambry Genetics

facial dysmorphism-immunodeficiency-livedo-short stature syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014058

Submitter: Ambry Genetics

IMAGe syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013873

Submitter: Orphanet

facial dysmorphism-immunodeficiency-livedo-short stature syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014058

Submitter: PanelApp Australia

colorectal cancer, susceptibility to, 12STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014038

Submitter: Labcorp Genetics (formerly Invitae)

POLE-related polyposis and colorectal cancer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100287

Submitter: PanelApp Australia

intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032684

Submitter: PanelApp Australia

facial dysmorphism-immunodeficiency-livedo-short stature syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014058

Submitter: Orphanet

colorectal cancer, susceptibility to, 12STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014038

Submitter: Genomics England PanelApp

Polymerase proofreading-related adenomatous polyposisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018653

Submitter: Orphanet

Clinical Genomic Database (CGD)

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Oncologic

Intervention: Allergy/Immunology/Infectious; Endocrine; Oncologic

Rationale: 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

Comments: In Colorectal cancer, susceptibility to, individuals have been described such that the presence of variants would warrant surveillance in the pediatric period

Refs: 14760276; 16835919; 23230001; 23263490; 24501277; 25370038; 30503519

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POLE variants in ClinVar

35 Conditions Cataloged

not providedTotal: 9057

Hereditary cancer-predisposing syndromeTotal: 6409

not specifiedTotal: 1189

Colorectal cancer, susceptibility to, 12Total: 1044

Facial dysmorphism-immunodeficiency-livedo-short stature syndromeTotal: 391

POLE-related disorderTotal: 335

Intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiencyTotal: 332

Polymerase proofreading-related adenomatous polyposisTotal: 150

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006231.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous		2 clinvar	74 clinvar	2326 clinvar	27 clinvar	2429
missense	3 clinvar	16 clinvar	4980 clinvar	506 clinvar	4 clinvar	5509
nonsense	78 clinvar	98 clinvar	38 clinvar			214
start loss	1 clinvar	5 clinvar	4 clinvar			10
frameshift	232 clinvar	137 clinvar	117 clinvar			486
splice donor/acceptor (+/-2bp)	7 clinvar	160 clinvar	53 clinvar	2 clinvar		222
Total	321	418	5266	2834	31	8870

Highest pathogenic variant AF is 0.0000818118

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 21 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006231.4	RefSeq	NP_006222.2	49	MANE Select
ENST00000320574.10	Ensembl	ENSP00000322570.5	49	MANE Select
ENST00000434528.5	Ensembl	ENSP00000500921.1	2	Standard
ENST00000441786.3	Ensembl	ENSP00000480727.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

Biological Process

G1/S transition of mitotic cell cycle
mitotic cell cycle
DNA synthesis involved in DNA repair
DNA replication
leading strand elongation

Molecular Function

nucleotide binding
DNA binding
chromatin binding
DNA-directed DNA polymerase activity
protein binding

Cellular Component

nucleus
nucleoplasm
plasma membrane
epsilon DNA polymerase complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000320574
Coding exons: 49
Length: 63604
Individuals with no LoFs: 125571
Homozygous LoFs: 0
Heterozygous LoFs: 177
Defined: 125748
p: 0.000704

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.07	1287	1.40e+3	0.920	0.0000912	15040
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00087	0.00086	rare
Latino/Admixed American	0.00087	0.00087	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00082	0.00082	rare
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.00078	0.00076	rare
South Asian	0.00065	0.00065	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

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.;

Intolerance Scores

LoFtool: 0.864
RVIS EVS: -0.81
RVIS percentile EVS: 12.09

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.997

Gene Damage Prediction

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