PTEN – genetic testing

PTEN genetic testing should be considered in individuals:^r

• who meet revised PTEN hamartoma tumour syndrome (PHTS) clinical diagnostic criteria^r*
• who have a relative who meets revised PHTS clinical diagnostic criteria for whom testing has not been performed AND
  • any two major criteria OR 
  • one major and two minor criteria OR 
  • three minor criteria^r
• who have a Cleveland score of ≥15 (see Risk calculator for estimation of PTEN mutation mutation probability)
• where a known germline pathogenic variant is identified in a relative* 
• where a specific pathogenic variant has been identified on somatic tumour testing *
• who meet testing criteria for a relevant gene panel and there is relevant PTEN-specific phenotype (e.g. breast cancer panel, macrocephaly with developmental delay).

*In these settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective.

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).

* 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 PHTS^r
• 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 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 cohort^r although this has not been validated in an independent dataset.

A range of testing methodologies are needed to identify pathogenic changes in the PTEN gene including:

• sequencing
• copy number analysis.

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

Result	Reference databases	Considerations and advice
Pathogenic variant search
Pathogenic variant	ClinVar LOVD	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

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Version 8

Date

Summary of changes

23/01/2023

The following sections of the document were updated to align with the new eviQ cancer genetics genetic testing template: Target population:  Added "where a specific pathogenic variant has been identified on somatic tumour testing *" Added "*In these settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective." "a patient's choice" removed from "The decision to offer a genetic test should be based on the pre­test probability of identifying a heritable pathogenic variant and the performance of the test (e.g. false negative rate)." Probability of a heritable pathogenic variant Removed "rather than being inherited" from the sentence "The rate of pathogenic variants that arise de novo rather than being inherited is unknown." Circumstances in which testing is not indicated:  Removed "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." Testing methods: Added "A variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective where a relative is known to have a germline pathogenic variant or a pathogenic variant has been identified in the patient’s tumour." Removed "MLPA" Result interpretation: HGMD and DMuDB removed from table. Template sentence added. Version increased to V.8.

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.