• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)
  • Alternate specimens:
    Saliva, assisted saliva, buccal swab and gDNA
  • Sample requirements
  • Request a sample kit




Associated disorders

The POLE gene is associated with an autosomal dominant predisposition to colonic adenomatous polyps and colon cancer (PMID: 23263490, 26133394, 23585368, 24501277, 24788313) and autosomal recessive FILS syndrome (facial dysmorphism, immunodeficiency, livedo, and short stature) (MedGen UID: 767490).

The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, an enzyme that plays a critical role in DNA replication and repair.

POLE heterozygotes
MedGen UID: 430218

Clinical condition
Pathogenic variants in the POLD1 and POLE genes are associated with a recently defined, highly penetrant autosomal dominant colorectal cancer predisposition syndrome whose proposed name is polymerase proofreading-associated polyposis syndrome (PPAP) (PMID: 24509466, 26133394, 25529843, 26822575). Individuals with a single pathogenic POLE variant typically have a more attenuated colorectal phenotype, regularly presenting before the age of 60 with colorectal cancer (often microsatellite stable) or fewer than 100 adenomas (PMID: 25529843, 23263490, 24501277, 23585368). The clinical spectrum ranges from large polyps (>2 cm in diameter) to multiple adenomas resembling attenuated familial adenomatous polyposis (AFAP) to MUTYH-associated polyposis syndrome (MAP) (PMID: 25529843). Many cases may also have a family history of clustering of early-onset colorectal cancer similar to what is typically seen in Lynch syndrome (also called hereditary non-polyposis colorectal cancer, or HNPCC), although some have no such history (PMID: 25529843).

PPAP is associated with an increased risk of gastroduodenal (mostly duodenal) adenomas and malignancy; however, this risk appears limited to those with a POLE pathogenic variant (PMID: 26133394, 25529843, 24788313). Other reported extra-gastrointestinal findings observed in those with a pathogenic POLE variant include pilomatricomas, retroperitoneal fibrosis, lipoma, and fibromas (PMID: 25529843).

There is preliminary evidence suggesting women with PPAP may have an increased risk of endometrial cancer; however, this risk appears to be limited to those with a POLD1 pathogenic variant (PMID: 26133394, 25529843, 23263490, 26822575). The risk for other cancers may also be elevated; however, this evidence is limited and emerging (PMID: 23263490, 26133394, 25529843, 26822575). An individual with a POLE pathogenic variant will not necessarily develop cancer in their lifetime, but the risk of cancer is increased over the general population risk.

Gene information
The POLE gene plays a critical role in DNA replication and repair (Gene. Gene ID: 5426. http://www.ncbi.nlm.nih.gov/gene/5426 Accessed March 2018). POLE and POLD1 encode the catalytic and proofreading subunits of the polymerase enzyme complexes e (Pol d) and d (Pol e), respectively. These subunits are involved in synthesis regulation and cofactor binding (PMID: 25529843). If there is a pathogenic variant in this gene that prevents it from functioning normally, the risk of developing certain types of cancers is increased.

Hereditary predisposition to cancer due to pathogenic variants in the POLE gene has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. Once a pathogenic mutation is detected in an individual, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. Most cases are inherited from a parent, but some cases can occur spontaneously (i.e., an individual with a pathogenic variant has parents who do not have it) (PMID: 25529843). An individual with a variant in POLE has a 50% risk of passing that variant on to offspring.

The POLE gene has preliminary evidence supporting a correlation with autosomal recessive facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome (PMID: 23230001, 25948378). FILS is an autosomal recessive condition that is characterized by mild facial dysmorphism, immunodeficiency resulting in recurrent infections, livedo on the skin that is present at birth, and short stature. Malignancies have not been observed in affected individuals (PMID: 23230001, 25948378)). For there to be a risk of FILS in offspring, a patient and their partner would each have to have a single pathogenic variant in POLE; in such a case, the risk of having an affected child is 25%.

Medical management and surveillance protocols for individuals with a pathogenic variant in POLE have been developed by the National Comprehensive Cancer Network® (NCCN) (NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High-Risk Assessment: Colorectal. Version 3.2017):

  • Begin colonoscopy at 25-30 years of age
    • If negative, continue colonoscopy every 2-3 years thereafter.
    • If polyps are found, colonoscopy is recommended every 1-2 years with consideration of surgery if the polyp burden becomes unmanageable by colonoscopy.
  • Surgical evaluation, if appropriate.

Bellido et al. and Spier et al. have also proposed surveillance guidelines that include screening for gastroduodenal malignancies (PMID: 26133394, 25529843):

  • colonoscopies every 1–2 years starting at age 18–25 years
  • gastroduodenoscopy at least every three years (in the case of normal findings), beginning at 20–30 years of age
  • consideration of prophylactic colectomy (the timing and extent of such invasive interventions has yet to be determined) (PMID: 25529843))

Because endometrial cancer has so far only been reported in individuals with POLD1 pathogenic variants, no specific surveillance regarding endometrial cancer screening is currently suggested for those with a pathogenic variant in POLE (PMID: 26133394, 25529843)).

An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.

Knowing if a pathogenic variant is present in POLE is advantageous. At-risk relatives can be identified, enabling pursuit of a diagnostic evaluation. Further, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant data regarding POLE are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow published screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.

Additional reference
Referenced with permission from the NCCN Genetic/Familial High-Risk Assessment: Colorectal. Version 3.2017. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed February 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.

The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.

Review date: March 2018

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
POLE NM_006231.3