• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit




Associated disorders

The POLD1 gene is associated with an increased risk for autosomal dominant colonic adenomatous polyps and colon cancer (PMID: 24509466), and autosomal dominant mandibular hypoplasia, deafness, progeroid features, and lipodystrophy (MDPL) syndrome (MedGen UID: 811623).

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The POLD1 gene encodes the catalytic subunit of DNA polymerase delta, an enzyme that plays a critical role in DNA replication and repair.

POLD1 heterozygotes
MedGen UID: 436445

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 POLD1 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). 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; however, malignancy appears to be limited to those with a POLE pathogenic variant (PMID: 26133394, 25529843, 24788313, 26822575). An individual with a POLD1 pathogenic variant will not necessarily develop cancer in their lifetime, but the risk for cancer is increased over the general population risk.

There is preliminary evidence suggesting those with a single pathogenic variant in this gene may have a predisposition to develop endometrial cancer (PMID: 26133394, 25529843, 23263490, 26822575). These data, however, are currently insufficient to make a clear determination regarding this association. Therefore POLD1 is considered a “preliminary-evidence” gene and is available on Invitae’s Breast and Gyn Cancers Panel. Preliminary-evidence genes are selected from an extensive review of the literature and expert recommendations, but the association between the gene and the specific condition has not been completely established. This uncertainty may be resolved as new information becomes available, and therefore clinicians may continue to order these preliminary evidence genes. The risk for other cancers may also be elevated; however, this evidence is limited and emerging (PMID: 26133394, 25529843, 23263490, 26822575).

Gene information
The POLD1 gene plays a critical role in DNA replication and repair (Gene. Gene ID: 5424. http://www.ncbi.nlm.nih.gov/gene/5424 Accessed March 2018). POLD1 and POLE 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 POLD1 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 POLD1 has a 50% risk of passing that variant on to offspring.

POLD1 is also associated with autosomal dominant mandibular hypoplasia, deafness, progeroid features and lipodystrophy (MDPL) syndrome (MedGen UID: 811623). MPDL is a rare, systemic disorder that is characterized by loss of subcutaneous fat, distinctive facial features, and metabolic abnormalities including insulin resistance and diabetes. Sensorineural hearing loss typically occurs late in the first or second decades of life (PMID: 25131834, 23770608).

Medical management and surveillance protocols for individuals with a pathogenic variant in POLD1 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 and endometrial 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
  • endometrial cancer screening for women beginning at age 40
  • consideration of prophylactic colectomy (the timing and extent of such invasive interventions has yet to be determined) (PMID: 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 POLD1 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 POLD1 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. In addition, the analysis covers the select non-coding variants specifically defined in the table below. 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
POLD1 NM_002691.3