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MEN1 and CDKN1B – genetic testing

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Genetic testing for multiple endocrine neoplasia type 1 (MEN1):

  • An individual who meets criteria for a diagnosis of MEN1
  • An individual with parathyroid hyperplasia or adenoma before age 40 years
  • An individual with recurrent or multiglandular primary hyperparathyroidism at any age
  • An individual with familial isolated hyperparathyroidism (FIHPT)
  • An individual with a gastrinoma or multifocal gastroduodenopancreatic NET (GDP-NET^) at any age OR a unifocal GDP-NET^ before age 40 years
  • An individual with a bronchial or thymic NET at any age
  • Where a known germline pathogenic variant is identified in a first-degree relative*
  • Where a specific pathogenic variant has been identified on somatic tumour testing*

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

^GDP-NET includes nonfunctional GDP-NET, gastrinoma, insulinoma, glucagonoma, somatostatinoma and vasoactive intestinal peptide secreting NET (VIPoma).

Genetic testing for CDKN1B should be considered in:

  • An individual who meets testing criteria for MEN1 and genetic testing for MEN1 is uninformative OR
  • An individual who meets testing criteria for MEN1 and panel testing is being done
  • Where a known germline pathogenic variant is identified in a first-degree relative*
  • Where a specific pathogenic variant has been identified on somatic tumour testing*

*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 pre­test probability of identifying a heritable pathogenic variant and the performance of the test (e.g. false negative rate).

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant in the MEN1 gene associated with MEN type 1 syndrome:

  • verification of pathology and radiology
  • biochemical assessment for primary hyperparathyroidism (serum calcium, parathyroid hormone), functioning pituitary adenoma (e.g. prolactin, IGF-1), functioning GDP-NET (fasting glucose, insulin, gastrin, glucagon, VIP) or other additional testing congruent with the clinical presentation
  • if hypercalcaemic, calcium creatinine clearance ratio (fractional calcium excretion) to exclude familial hypocalciuric hypercalcemia (FHH): to use the Hammersmith Urine Calcium: Creatinine Clearance Calculator, right click on the link, choose 'Copy link address' and paste it into a new browser, which will download the calculator spreadsheet

Of the heritable pathogenic variants identified in the MEN1 gene, approximately 10% are de novo.

Factors Probability of detecting a heritable MEN1 pathogenic variant
Clinical diagnosis of MEN type 1 syndrome and family history of MEN1 tumours 80-90%r
Clinical diagnosis of MEN type 1 syndrome and no family history of MEN1 tumours 65%r
Isolated parathyroid adenoma before age 40 5-13%r
Familial isolated hyperparathyroidism (FIHPT) Up to 20%r
Pituitary adenoma Up to 3%r
Isolated gastrinoma (any age) 5-25%rr
Isolated insulinoma (any age) 4%r
Bronchial NET (any age) 5-10%r
Thymic NET (any age) 25%r
Patient has a first or second degree relative with documented pathogenic variant Up to 50%

Due to the small number of cases of MEN4 syndrome described in the literature the tumour-specific probabilities of detecting a heritable CDKN1B pathogenic variant have not yet been determined. Current estimates suggest the incidence of CDKN1B pathogenic variants in patients with a MEN1-related phenotype is 1.5-3.7%.r

Genetic testing is not indicated in the following circumstances:

  • An individual who does not fit within the target population
  • Individuals with an isolated key MEN1-related tumour developing after age 40 years (with the exception of gastrinoma or multifocal GDP-NET) and no family history of MEN1 tumours, as they rarely have MEN1 pathogenic variantsr
  • Individuals with an isolated non-key MEN1-related tumour (such as ileal NETs or adrenal tumour) and no family history of MEN1 tumours (with the exception of bronchial or thymic NET), as they rarely have germline MEN1 pathogenic variants.r

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

A range of testing methodologies are needed to identify pathogenic changes in the MEN1 gene including:

  • DNA sequencing
  • copy number analysis 

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.

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 should be considered.

If genetic testing in DNA from peripheral blood does not identify a pathogenic variant, testing of other tumour and tissue samples may be indicated to assess for mosaicism.

Result Reference databases Considerations and advice
Pathogenic variant search
Pathogenic variant

ClinVar

UMD

LOVD

 MEN1 or CDKN1B – 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   MEN1 or CDKN1B – risk management
Family pathogenic variant not found   Screening based on 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 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 9

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: 
    • MEN1 
      • 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."
    • CDKN1B:
      • Added "Where a known germline pathogenic variant is identified in a first-degree relative *"
      • 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."
    • Edited: " 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)." to remove "patient's choice".
  • 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. MLPA, Sanger sequencing"
  • Result interpretation:
    • HGMD and DMuDB removed from table.
    • Template sentence added.

Version increased to V.7. 

Version 8

Date Summary of changes
26/11/2021

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

Target population:

  • 'Genetic testing for multiple endocrine neoplasia type 1 (MEN 1):' inserted
  • Bullet 2: moved down list
  • Bullets 5 and 6 combined and reworded as: 'An individual with a gastrinoma or multifocal gastroduodenopancreatic NET (GDP-NET*) at any age OR a unifocal GDP-NET* before age 40 years'
  • Bullet 7: 'first-degree' inserted
  • 'Genetic testing for CDKN1B should be considred in:' inserted

Investigations before genetic testing: 

  • Opening sentence: 'syndrome' inserted
  • Bullet 1: 'previous' deleted
  • Bullet 2 changed to read: 'biochemical assessment for primary hyperparathyroidism (serum calcium, parathyroid hormone), functioning pituitary adenoma (e.g. prolactin, IGF-1), functioning GDP-NET (fasting glucose, insulin, gastrin, glucagon, VIP) or other additional testing congruent with the clinical presentation'
  • Bullet 3 changed to read: 'if hypercalcaemic, calcium creatinine clearance ratio (fractional calcium excretion) to exclude familial hypocalciuric hypercalcemia (FHH): see Hammersmith Urine Calcium: Creatinine Clearance Calculator'

Probability of a heritable pathogenic variant: 

  • Table column 2 title: 'MEN1' inserted
  • Row 1: '+' changed to 'syndrome and'
  • Row 2: 'syndrome' inserted
  • New row 'Pituitary adenoma' inserted
  • Rows reordered and references updated throughout
  • Inserted: 'Due to the small number of cases of MEN4 syndrome described in the literature the tumour-specific probabilities of detecting a heritable CDKN1B pathogenic variant have not yet been determined. Current estimates suggest the incidence of CDKN1B pathogenic variants in patients with a MEN1-related phenotype is 1.5-3.7%.'

Circumstances in which testing is not indicated: 

  • New bullet 1 inserted
  • Bullet 2: 'only one' changed to 'an isolated'

Testing methods: 

  • Bullet 1: 'DNA' inserted
  • Removed link to European Directory of DNA Diagnostic Laboratories

Website resources inserted

Version number increased to V.8. Review in two years.

Version 7

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 "25% or 50%" to "Up to 50%"
  • Circumstances in which testing is not indicated: template wording updated
  • Testing methods: template wording added
  • Result interpretation: table format updated. Reference databases added. Template sentences added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • Website resources: section deleted
  • Version number increased to V.7.

Version 6

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.6.

Version 5

Date Summary of changes
29/05/2013 Discussed at March 6, 2013 reference committee meeting and following further email review approved for publication.
26/03/2014

Following discussion at March 5, 2014 reference committee meeting the following change has been made:

  • Diagnostic testing - Link to Human Genetics Society of Australasia removed.
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.
04/01/2016 Discussed at October 2014 reference committee meeting, and following further email review approved for publication. 
31/05/2017 Transferred to new eviQ website. Version number changed to V.3.
08/10/2018

Presented at May 2018 RCM and discussion continued over email. Approved for publication with the following changes:

  • Version number changed to V.4. 
  • Target population:
    • Bullet added - bronchial or thymic NET
    • GEP-NET defined
  • Investigations before genetic testing: 'previous' added to first bullet. Second and third bullets updated to include more information.
  • Probability of a heritable mutation: table figures, references updated and conditions added.
  • Circumstances in which testing is not indicated: updated to include more information.
  • Testing methods: section amended to reflect newer GT template.
  • Results interpretation:
    • ​​​Reference databases changed from ARUP and HGMD to Clin Gen.
    • Considerations and advice changed for inconclusive result.
    • RM protocol linked into considerations and advice column of Predictive testing: Family mutation identified
  •  References: Updated
08/03/2019

Protocol updated offline on advice from endocrinologists, and approved with the following changes made:

  • All mentions of 'gastroenteropancreatic NET (GEP-NET)' changed to 'gastoduodenopancreatic NET (GDP-NET)'.
  • Version kept at V.4. and review dates to remain the same.
28/08/2019 Protocol title changed from 'Genetic testing for heritable mutations in the multiple endocrine neoplasia (MEN) 1 gene' to 'MEN1 genetic testing' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.5.

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/1428

13 Oct 2024