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RET (MEN2) – genetic testing

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  • An individual who meets clinical diagnosis criteria for multiple endocrine neoplasia type IIa (MEN2A) or multiple endocrine neoplasia type IIb (MEN2B, sometimes also referred to as MEN3)
  • An individual diagnosed with medullary thyroid cancer (MTC)
  • An individual diagnosed with paraganglioma or phaeochromocytoma (PC)
  • An individual with primary hyperparathyroidism (PHPT) before age 40 years*
  • An individual with recurrent or multiglandular primary hyperparathyroidism at any age*
  • Where a known germline pathogenic variant is identified in a relative**
  • Where a specific pathogenic variant has been identified on somatic tumour testing**

*Testing of a panel of genes may be considered in the context of a diagnosis of parathyroid disease only.

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

Genetic testing is recommended for good clinical care of individuals who are suspected of having a heritable pathogenic variant in this gene.

Because early detection of at-risk individuals affects medical management, testing of asymptomatic children is recommended. This should occur as soon as possible after birth in MEN2B and usually before age 5 in MEN2A.r

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

  • verification of pathology
  • biochemical assessment for primary hyperparathyroidism or phaeochromocytoma (plasma or urinary metanephrine and normetanephrine).

Of the heritable pathogenic variants identified in the RET gene, approximately 5% are de novo in MEN2A and 75% are de novo in MEN2B.r

Factors Probability of detecting a heritable pathogenic variant
Medullary thyroid cancerr 25-30%
MEN2A clinical diagnosis 95%
MEN2B clinical diagnosis  98%
MTC and no family history 7%*r
Phaeochromocytoma and no family history or syndromic featuresr  5%
PHPT and no family historyr <1%
Patient has a first or second degree relative with documented pathogenic variant Up to 50%

*genetic testing still indicated despite <10% genetic testing yield because of the opportunity for risk-reducing thyroidectomy

Testing is not indicated in non-medullary thyroid cancer.

Predictive testing should never be ordered for a variant of uncertain significance or a benign/likely benign variant.

The following testing methodology detects almost all pathogenic changes in the RET gene that are associated with MEN2:

  • Sequencing

Information about DNA tests and testing laboratories is available from: 

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.

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.

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant

ClinVar

LOVD

ATA guidelinesr

 RET (MEN2) – risk management
Variant of uncertain significance

There may still be a residual risk and management advice applies

Review pathogenicity of variant 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   RET (MEN2) – 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 variant of uncertain significance is identified, consider referral to a clinical genetics service or familial cancer centre for review and guidance.

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
28/02/2024

Protocol reviewed at March 2023 reference committee meeting. Discussions continued via Teams. Approved for publication with the following changes made: 

  • Target population: updated
  • Probability of a heritable pathogenic variant: addition of 'MTC and no family history' and 'PHPT and no family history'.
  • Result interpretation: Link to ARUP removed as no longer available. 

Version number changed to V.7. 

Version 6

Date Summary of changes
20/02/2023

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."
  • Probability of a heritable pathogenic variant:
    • Removed first sentence "The frequency of heritable pathogenic variants..."
  • 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 "e.g. Sanger sequencing"
  • Result interpretation:
    • HGMD and DMuDB removed from table.
    • Template sentence added.

Version increased to V.6. 

Version 5

Date Summary of changes
28/01/2021

Protocol reviewed at November 2018 and May 2019 cancer genetics reference committee meetings. Discussions continued via email. Approved for publication with the following changes made: 

  • Related pages: added link to "Guide for health professionals ordering genetic testing". Removed link to "Pre-test counselling"
  • Target population: minor wording changes
  • Probability of a heritable pathogenic variant: minor wording changes. 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 sentences added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • "Mutation" changed to "pathogenic variant" and "unclassified variant" changed to "variant of 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 changed to V.5. Review in 2 years.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 4

Date Summary of changes
29/05/2013 Discussed at March 6, 2013 reference committee meeting and following further email review approved for publication.
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.
23/06/2016

Discussed at the October 23, 2015 reference committee meeting and further email review, the following changes were made and approved:

  • Target population - genetic testing comments amended.
  • Factors which influence pre-test probability - figures and references updated, table references updated.
  • Circumstances in which testing not indicated - no family history deleted.
  • Diagnostic testing - format updated as per new genetic testing protocol template.
  • Websites - AMEND added
  • References - updated
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.
23/04/2019 Links in Probablility of a heritable mutation section updated to 'Genetic testing for heritable mutations in the von Hippel-Lindau (VHL) gene' and 'Panel testing for heritable mutations in paraganglioma-phaeochromocytoma genes' to reflect updated titles/protocols.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the RET gene associated with (MEN) type 2' to 'RET (MEN2) 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/1429

10 Sep 2024