Version July 2025
INTRODUCTION —
This monograph summarizes the interpretation of germline testing of the POLD1 and POLE (also known as POLE1) genes. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately [1].
OVERVIEW
How to read the report — The tables provide a checklist for reviewing a genetic test report (table 1) and a glossary of terms that may be used (table 2).
Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).
●Genotype – Identifies variation from a reference sequence. If the results were obtained by direct-to-consumer testing or a research study and would impact clinical care, testing should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory or other nationally certified laboratory. This includes a positive finding, regardless of clinical presentation, or a negative finding in an individual with a suspected cancer syndrome or a positive family history of a cancer syndrome.
●Interpretation – Pathogenicity (ability to cause disease) is determined based on preclinical, clinical, and epidemiologic studies. The table summarizes the five classifications (table 3).
It is critical that the interpretation apply to the specific condition (for hereditary colorectal cancer, polymerase proofreading-associated polyposis [PPAP]).
A variant of uncertain significance (VUS) is one for which the association with disease is currently unknown; additional study will eventually determine if the variant is pathogenic or benign. Periodic reassessment of available information is appropriate.
●POLD1 and POLE-specific caveats – For both POLD1 and POLE, the site of pathogenic variants within the gene is critical, with different variants associated with different conditions.
•Pathogenic variants and likely pathogenic variants in the exonuclease domains of these genes are rare causes of hereditary colorectal cancer, and many variants have not been fully characterized. The exonuclease domains are responsible for the enzymes' proofreading function.
•Pathogenic variants in the region of POLD1 that encode the enzyme's active site cause an autosomal dominant progeria syndrome [2,3]. (See 'MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome)' below.)
•Pathogenic variants in POLE that cause loss of function or reduced function and are inherited in an autosomal recessive manner cause a different spectrum of conditions including FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) and IMAGE-I (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency) [4-7]. (See 'FILS and IMAGE-I' below.)
Understanding this information is required for thoughtful discussions about the risks for the tested individual, advice about management, reproductive counseling, and testing of first-degree relatives. If there are questions, referral to a genetics expert may be helpful. (See 'Genetics experts' below.)
Functions of POLD1 and POLE genes — POLD1 and POLE encode deoxyribonucleic acid (DNA) polymerase components.
●POLD1 encodes the catalytic and proofreading subunit of DNA polymerase delta, which is used in DNA replication.
●POLE encodes DNA polymerase epsilon, which is used in DNA repair and possibly in DNA replication.
Pathogenic and likely pathogenic variants associated with polymerase proofreading-associated polyposis (PPAP) generally cluster in the exonuclease domain of the polymerase. These variants interfere with the proofreading function of the polymerases and lead to mismatch repair (MMR) deficiency, similar to variants in Lynch syndrome genes. (See "Lynch syndrome (hereditary nonpolyposis colorectal cancer): Clinical manifestations and diagnosis", section on 'Genetics'.)
Disease associations
PPAP (polymerase proofreading-associated polyposis) — Pathogenic variants in the POLD1 and POLE exonuclease domain interfere with the proofreading capacity of the polymerase and cause an autosomal dominant colorectal adenomatous polyposis syndrome referred to as polymerase proofreading-associated polyposis (PPAP) [8,9]. Individuals who are heterozygous for a pathogenic variant in one of these genes can develop numerous colonic polyps (typical range, 30 to 100 adenomas) and other cancers [10,11].
Pathogenic or likely pathogenic variants in POLD1 and POLE are associated with the following PPAP-associated increased risks [10]:
●Colorectal cancer (absolute risk >20 percent).
●Duodenal adenomas and duodenal carcinomas.
●Possible increased risk of endometrial cancer, although this is not well-established.
●Possible increased risk of ovarian cancer with POLE variants.
●Risks of other cancers are unclear.
While PPAP is phenotypically similar to familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP), it is molecularly more similar to Lynch syndrome, which is characterized by MMR deficiency. The implications are that surveillance is similar to FAP and MAP (see 'Individuals without cancer' below), but cancer treatment takes advantage of sensitivity to immune checkpoint inhibitors. (See 'Individuals with cancer' below.)
MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome) — MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome) is a separate syndrome unrelated to PPAP, due to a recurrent de novo mutation in POLD1 that affects the polymerase activity of the enzyme, leaving exonuclease activity decreased but intact.
Details of the clinical features and evaluation are presented separately. (See "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis", section on 'Mandibular hypoplasia, deafness, and progeroid features syndrome' and "Werner syndrome", section on 'MDPL syndrome'.)
FILS and IMAGE-I — Two autosomal recessive conditions are associated with specific pathogenic variants in POLE that cause loss of function or reduced function:
●FILS (facial dysmorphism immunodeficiency and short stature) [4,6].
●IMAGE-I (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency) [5,7].
IMPLICATIONS FOR THE TESTED INDIVIDUAL
Individuals without cancer
Pathogenic or likely pathogenic variant — We consider all individuals with a likely pathogenic variant or pathogenic variant meeting specific criteria in POLD1 or POLE to be at risk for polymerase proofreading polyposis (PPAP), regardless of the initial reason for testing.
Counseling may require additional visits or referrals. Acting upon genetic test results is rarely an emergency; the individual can be reassured that management decisions can be deferred until questions are answered.
Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for relatives. (See 'At-risk relatives' below.)
In addition to annual physical examinations, several evaluations and interventions are recommended to reduce the risk of associated cancers (table 4).
We adhere to National Comprehensive Cancer Network (NCCN) recommendations for surveillance and risk reduction [10]. Findings in relatives (type of cancers, age of onset) may also inform surveillance (starting at an earlier age if a relative has an earlier age of onset).
●Colorectal cancer screening/surveillance:
•High-quality colonoscopy starting at age 25 to 30 years. Repeat every two to three years if negative and every one to two years if polyps are identified. May be initiated earlier (during late childhood) if the family history shows polyps at a younger age. In such a case, colonoscopy would be initiated two to five years before polyps appeared in first-degree relatives.
•Polypectomy when feasible, followed by colonoscopy as above.
•Colectomy for any of the following (algorithm 1):
-Documented or suspected colorectal cancer
-Severe symptoms (eg, gastrointestinal bleeding)
-Marked increases in polyp number on consecutive examinations
-Inability to adequately survey the colon because of multiple polyps
•Following colectomy with ileorectal anastomosis or with ileal pouch-anal anastomosis (IPAA), endoscopic evaluation of the rectum or ileal pouch every 6 to 12 months depending on polyp burden. Following total proctocolectomy with end-ileostomy, annual endoscopic examination of the ileostomy.
●Duodenal cancer screening/surveillance – Duodenal polyps generally develop after colonic polyps. Surveillance generally starts at age 25 to 30 years and is repeated approximately every three years.
●Other cancer risks – Routine screening is not recommended for other cancers such as pancreatic, ovarian, endometrial, or central nervous system. However, the decision to screen should be individualized based on family history.
Negative testing — Negative testing means no pathogenic variants were identified. However, some tests only evaluate a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes.
●If the familial POLD1 or POLE variant is known and the tested individual does not have that variant, usually they can be reassured that they are not at high risk for associated polyposis and cancers, with caveats outlined above. (See 'How to read the report' above.)
However, it is important to provide an individualized risk assessment based on family history and other risk factors.
●If a familial variant is not known and results of genetic testing are negative, additional risk factors (genetic or acquired) may be present, and additional testing with a colorectal cancer gene panel or other genetic testing may be indicated. Surveillance is based on family history and other risk factors. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong family history of cancer.
Variant of uncertain significance (VUS) — Individuals with a VUS should be managed based on their personal and family history and not the VUS.
New information may become available; the testing laboratory or other resources should be consulted periodically for updates (eg, annually). (See 'How to read the report' above.)
Individuals with cancer — The implications of genetic testing results should be discussed with the individual's oncologist or surgeon; referral to a specialist in hereditary colorectal cancer syndromes may be appropriate (table 4). (See 'Genetics experts' below.)
The presence of a likely pathogenic variant or pathogenic variant in POLD1 or POLE may impact several aspects of management; examples include:
●For colorectal cancer, more extensive colectomy (eg, total colectomy with ileorectal anastomosis or proctocolectomy) to reduce the risk of metachronous cancers based on patient age and rectal polyp burden. (See "Familial adenomatous polyposis: Screening and management of patients and families", section on 'Colectomy'.)
●Use of an immune checkpoint inhibitor such as a programmed death ligand 1 (PDL1) inhibitor. (See "Second- and later-line systemic therapy for metastatic gastric and esophageal cancer" and "Overview of advanced unresectable and metastatic solid tumors with DNA mismatch repair deficiency or high tumor mutational burden", section on 'Treatment'.)
Counseling and testing of first-degree relatives with cascade testing are appropriate. (See 'At-risk relatives' below.)
For individuals with a negative test or a VUS who have reasons to be concerned about a genetic cause, additional genetic testing of these genes or other colorectal cancer genes (such as in a colorectal cancer gene panel) may be appropriate. This may be discussed with a genetic counselor, the primary oncologist, or other hereditary colorectal cancer specialists. (See 'Genetics experts' below.)
Individuals with MDPL syndrome — MDPL syndrome (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy) is an autosomal dominant syndrome that can occur with certain POLD1 pathogenic variants.
These individuals are managed by specialty centers. (See "Lipodystrophy syndromes: Clinical manifestations, classification, and diagnosis", section on 'Mandibular hypoplasia, deafness, and progeroid features syndrome' and "Werner syndrome", section on 'MDPL syndrome'.)
Individuals with FILS or IMAGE-I — FILS (facial dysmorphism, immunodeficiency, livedo, and short stature) and IMAGE-I (intrauterine growth retardation, metaphyseal dysplasia, adrenal hypoplasia congenita, genital anomalies, and immunodeficiency) are autosomal recessive syndromes that can occur with certain pathogenic variants in POLE.
These individuals are typically managed in academic centers by multiple specialists. Referral information can be obtained from local genetics clinics or academic centers. (See 'Genetics experts' below.)
REPRODUCTIVE COUNSELING —
Counseling is appropriate for individuals with a pathogenic or likely pathogenic variant in POLD1 or POLE who are considering childbearing.
Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)
AT-RISK RELATIVES —
Individuals with a pathogenic variant or likely pathogenic variant in POLD1 or POLE should inform their at-risk relatives about the importance of genetic counseling and possible testing.
●The risk of having inherited the variant is 50 percent for first-degree relatives.
●Usually, the variant segregates on the side of the family with a history of cancer; however, if possible, it is recommended to test an affected individual (with polyposis or cancer) to ensure that the variant segregates with disease in the kindred.
●Genetic testing is generally deferred until adulthood to allow full informed consent, although some individuals in kindreds with earlier-onset disease may require testing at an earlier age. Considerations regarding the testing of minors are discussed separately. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues'.)
RESOURCES
UpToDate topics
●Colorectal cancer
•Genetics – (See "Molecular genetics of colorectal cancer".)
•Screening – (See "Screening for colorectal cancer in patients with a family history of colorectal cancer or advanced polyp", section on 'High-risk familial colorectal cancer syndromes'.)
•Selected guidelines – (See "Society guideline links: Hereditary colorectal cancer syndromes".)
●Genetics
•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)
•Terminology – (See "Genetics: Glossary of terms".)
•Testing – (See "Genetic testing".)
•Counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)
Genetics experts
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)
●Genetic counselors – National Society of Genetic Counselors (NSGC)
