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PTEN – genetic testing

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PTEN genetic testing should be considered in individuals:r

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.

* Additional clinical judgement may be necessary when applying these criteria to paediatric and early adult patients, where features necessary to meet diagnostic criteria may not yet all be present.r For paediatric cases, consider using the Cleveland Clinic PTEN paediatric clinical criteria for testing.r PTEN testing should also be considered in children presenting with thyroid cancer, especially where macrocephaly co-exists.rr

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant in the PTEN gene:

  • consideration of the operational criteria for PHTSr
  • clinical examination for the detection of macrocephaly
  • clinical examination/biopsy for detection of dermatologic features especially trichilemmomas and oral papillomas.

The true frequency of clinical features in individuals with a PTEN pathogenic variant is currently not known.r

The rate of pathogenic variants that arise de novo rather than being inherited is unknown.

Heritable PTEN pathogenic variants are estimated to affect about 1 in 200,000 individuals, although this may be an underestimate given the difficulty in diagnosis presented by this highly variable disease and the fact that many component features in and of themselves can occur in the general population.r

Factors Probability of detecting a pathogenic variant
Patient who meets revised PTEN hamartoma tumour syndrome clinical diagnostic criteriar Up to 90%r
Patient has a first or second degree relative with documented pathogenic variant Up to 50%
Patient has a Cleveland score ≥15r 10%

Cleveland score ≥15 gives 10% mutation rate in the Eng cohortr although this has not been validated in an independent dataset.

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 are needed to identify pathogenic changes in the PTEN gene including:

  • sequencing
  • MLPA copy number analysis.

Gene-specific criteria for the interpretation of PTEN variants have been developed by the ClinGen PTEN Expert Panel.r

Information about DNA tests and testing laboratories is available from: 

If a decision is made to test this gene 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. 

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant

ClinVar

LOVD

HGMD

DMuDB

 PTEN (PTEN hamartoma/Cowden) – risk management
Variant of uncertain significance

Review pathogenicity of variants periodically

Identify other genes for which a pathogenic variant search could be considered
No reportable variant  

Identify other genes for which a pathogenic variant search could be considered 
Predictive testing
Family pathogenic variant identified   PTEN (PTEN hamartoma/Cowden) – risk management
Family pathogenic variant not found   Screening based on revised 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).

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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Version 7

Date Summary of changes
21/10/2021

Protocol reviewed at May 2021 cancer genetics reference committee meeting. Discussion continued via email and MS Teams. Approved for publication with the following changes made:

  • Target population:
    • moved bullet 2 down list, inserted new bullets 3 and 5
    • new sentence inserted at end of asterisked note: 'PTEN testing should also be considered in children presenting with thyroid cancer, especially where macrocephaly co-exists.'
  • Investigations before genetic testing: Links to images of trichilemmomas and oral papillomas removed due to limited clinical utility
  • Probability of a heritable pathogenic variant: new row inserted: 'Patient with a Cleveland score ≥15**: 10%' and new note: '** Cleveland score ≥15 gives 10% mutation rate in the Eng cohort although this has not been validated in an independent dataset.'
  • Testing methods: new sentence inserted: 'Gene-specific criteria for the interpretation of PTEN variants have been developed by the ClinGen PTEN Expert Panel.'
  • Result interpretation: variant of unknown significance: deleted 'Where clinical diagnostic criteria have been met, refer to PTEN (PTEN hamartoma/Cowden) - risk management'

Version number increased to V.7. Review in two years.

Version 6

Date Summary of changes
09/12/2020

The following sections of the document were updated to align with the new eviQ cancer genetics genetic testing template:

  • Related pages: added link to "Guide for health professionals ordering genetic testing". Removed link to "Pre-test counselling"
  • Probability of a heritable pathogenic variant: last row of table - probability changed from "50% or 25%" to "Up to 50%"
  • Circumstances in which testing is not indicated: template wording updated
  • Testing methods: template wording updated
  • Result interpretation: table format updated. Reference databases added. Template sentence added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • Website resources: section deleted
  • Version number increased to V.6.

Version 5

Date Summary of changes
18/11/2019
  • "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

Date Summary of changes
20/08/2012 Taken to reference committee.
10/10/2014 Approved and published.
30/09/2015 Sentence added to genetic testing protocol template: 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.
21/04/2017

Protocol discussed at the October 2016 reference committee meeting and review continued via email:

  • target population - updated
  • investigations which should be considered before germline genetic testing - updated (ACI images of trichilemmoams and oral papillomas added)
  • factors which influence the pre-test probability of a heritable mutation - table updated
  • diagnostic testing - updated as per template change
  • interpretation of mutation testing results - wording updated
  • references - updated.

Protocol republished, for review in 2 years. 
31/05/2017 Transferred to new eviQ website. Version number changed to V.3.
01/06/2018 'Gene Tests' link in Testing Methods section relabelled as GeneReviews.
05/06/2019

Protocol reviewed along with RM protocol (ID 546). Published with only the following changes made:

Probability of a heritable mutation, Circumstances in which testing is not indicated, Testing methods and Result interpretation sections: Updated with new changes from template review.

Version kept at V.3.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the PTEN gene' to 'PTEN 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. While eviQ endeavours to link to reliable sources that provide accurate information, eviQ and the Cancer Institute NSW do not endorse or accept responsibility for the accuracy, currency, reliability or correctness of the content of linked external information sources. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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https://www.eviq.org.au/p/1281

05 Feb 2023