POLE and POLD1 genetic testing

• Individuals with a personal history of colorectal cancer under the age of 50 years and/or >10 colorectal or upper gastrointestinal polyps who have been offered gene panel testing.
• Where a POLE or POLD1 pathogenic variant is identified in a relative.

The decision to offer a genetic test should be based on the pre-test probability of identifying a heritable pathogenic variant, the performance of the test (e.g. false negative rate), and the patient's choice.

The frequency of heritable pathogenic variants in the POLE and POLD1 genes is uncertain. In studies of highly selected individuals with familial CRC and/or significant polyposis and in whom pathogenic variants in other high risk genes such as the MMR genes, APC and MUTYH genes have been excluded, rates of 0.5 to 2.0% have been found.^rrr

The frequency of heritable pathogenic variants in the POLE and POLD1 genes in unselected individuals with CRC and/or polyposis is significantly less than 1%.^rrr

De novo pathogenic variants in POLE have been demonstrated but the de novo pathogenic variant rate in both POLE and POLD1 genes is unknown.^r

There is insufficient evidence to support routine testing of POLE and POLD1 outside the target group above.

A variant-specific test (rather than sequencing a single gene or gene panel) may be more cost effective and appropriate where: 

• a known pathogenic variant has been identified in a relative
• a specific pathogenic variant has been identified on somatic tumour testing. 

Predictive testing should never be ordered when only a variant of uncertain significance or a benign/likely benign variant has been identified in a family.

A range of testing methodologies may be needed to identify pathogenic changes in POLE and POLD1 genes including:

• sequencing
• copy number analysis (e.g. MLPA)

Information about testing and for laboratories is available from:

• RCPA catalogue of genetic tests and laboratories
• GeneReviews
• Genetic Testing Registry
• NHS National Genomic Test Directory

If a decision is made to test these genes as part of a cancer gene panel, care should be taken to select a panel where the individual genes tested have both clinical validity and clinical utility.

If this gene is tested using genomic sequencing (“next generation sequencing” or NGS), and testing has not identified a pathogenic variant, the value of testing using another methodology (e.g. MLPA, Sanger sequencing) should be considered.

If genetic testing in DNA from peripheral blood is uninformative, testing of two or more different tumour samples may be indicated to assess for mosaicism.

If a pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review, family risk notification and predictive testing.

If a mosaic pathogenic variant is identified refer to a clinical genetics service or familial cancer centre for review and guidance about the penetrance of phenotypic features (including cancer risk).

For additional information about the management of genetic test results when ordered by a non-genetic healthcare professional refer to eviQ’s Guide for health professionals ordering genetic testing.

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