PTEN genetic testing

PTEN genetic testing should be considered in individuals:^r

• who meet revised PTEN hamartoma tumour syndrome (PHTS) clinical diagnostic criteria^r*
• where a known pathogenic pathogenic variant is identified in a relative 
• who have a relative who meets revised PTEN hamartoma tumour syndrome clinical diagnostic criteria for whom testing has not been performed AND

i) any two major criteria; OR 
ii) one major and two minor criteria; OR 
iii) three minor criteria.^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

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 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

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

Information about DNA tests and testing laboratories is available from:

• RCPA catalogue of genetic tests and laboratories
• GeneReviews^®
• European Directory of DNA Diagnostic Laboratories
• Genetic Testing Registry
• NHS National Genomic Test Directory

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.

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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