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POLE and POLD1 genetic testing

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  • 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.

  • Nil

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 unknownr

Factors Probability of detecting a heritable pathogenic variant
Patient has a first or second degree relative with documented POLE or POLD1 pathogenic variant 25–50%

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

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:

If a decision is made to test this gene(s) 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.

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant ClinGen POLE or POLD1 (polymerase proofreading polyposis) - risk management
Inconclusive ClinGen Identify other genes for which a pathogenic variant search could be considered 
Predictive testing
Family pathogenic variant identified   POLE or POLD1 (polymerase proofreading polyposis) - risk management
Family pathogenic variant not found   Screening tailored based on a revised risk estimate 

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).

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Version 5

Date Summary of changes
19/11/2019
  • "Mutation" changed to "pathogenic variant" and "unknown significance" changed to "uncertain significance" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs 
  • Definition of "pathogenic variant" added as a pop-up

Version number increased to V.5.

Version 4

Dates Summary of changes
19/10/2016 Discussed at 10 March 2016 reference committee meeting and protocol finalised over email, with 2 yearly review.  
31/05/2017 Transferred to new eviQ website. Version number changed to V.2.
01/06/2018 'Gene Tests' link in Testing Methods section relabelled as GeneReviews.
24/04/2019

Protocol reviewed and presented at Nov 2018 cancer genetics RCM. Discussion continued over email and approved with the following changes made:

  • Title changed from Genetic testing for the heritable p.L424V mutation in the POLE gene and the p.s478N mutation in the POLD1 gene to Genetic testing for heritable mutations in the POLE gene and the POLD1 gene.
  • Target population: criteria updated.
  • Probability of a heritable mutation: Specific mutations removed from table.
  • Circumstance in which testing is not indicated: 'Predictive testing' sentence updated to align with template change.
  • Testing methods: first bullet updated to no longer include mention of specific mutations.
  • Result interpretation: 'Mutation search' section added in table. Link to risk management guideline added in predictive testing section. Sentences added below table to align with template change.

Version changed to V.3. To be reviewed in 2 years.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the POLE gene and the POLD1 gene' to 'POLE and POLD1 genetic testing' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.4.

The information contained in this document is based on the highest level of available evidence and consensus of the eviQ reference committee regarding their views of currently accepted approaches to care or treatment. Any clinician seeking to apply or consult this document is expected to use independent clinical judgement in the context of individual clinical circumstances to determine any patient's care or treatment. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/1912

03 Apr 2020