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CDKN2A – genetic testing

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  • A person with familial cutaneous melanoma, defined as a member of a cluster of three or more confirmed cases in first and second degree blood relatives, with ≥ 20% pre-test probability of a pathogenic CDKN2A variant using the four factor GenoMELPREDICTr score. (https://genomel.moffitt.org/GenoMELPREDICT)
  • Where a known germline pathogenic variant is identified in a relative*
  • Where a specific pathogenic variant has been identified on somatic tumour testing*
  • The inclusion of CDKN2A could be considered if panel gene testing is being offered to an individual with pancreatic cancer.

*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).

  • Confirmation of personal and family history.
  • Individuals with uveal or Spitzoid melanoma, consideration of assessment for BAP1.

The frequency of heritable pathogenic variant in the CDKN2A gene in unselected individuals with cutaneous melanoma is low (<1%) in Australia.r Heritable de novo pathogenic variants in the CDKN2A gene are rare.

The frequency of heritable pathogenic variants in the CDKN2A gene (affecting p16INK4A and/or p14ARF proteins) has been evaluated internationally by the GenoMEL Consortium, and its multivariate predictive model now replaces the previous MELPREDICT model developed in the US and Netherlands. The GenoMELPREDICT model performs well in Australian data, since one third of the dataset used to derive it came from Australian melanoma families with three or more cases.

Cases of uveal (internal eye) melanoma are not associated with CDKN2A pathogenic variants and should not be counted.

Factors Probability of detecting a heritable pathogenic variant** 
Person with 1 CMM*, diagnosed under aged 40 with no family history of CMM **1.4%r
Person with ≥2 CMMs, unselected for family history  **2.4%r
Person with 1 CMM at age 40, part of a cluster of 3 or more cases in first and second degree blood relatives  ***20.3%rr
Person with 3 CMMs, first diagnosed aged 40, part of a cluster of 3 or more cases in first and second degree blood relatives ***27%rr
Patient has a first or second degree relative with documented pathogenic variant Up to 50%

*CMM = cutaneous malignant melanoma (includes melanoma in-situ or invasive malignant melanoma of the skin)

**Data from Australian populations
***Probability of detecting a heritable pathogenic variant using four factor GenoMELPREDICT.  The probability of detecting a heritable CDKN2A pathogenic variant is also modestly inversely correlated with the underlying population risk (incidence) of cutaneous melanoma. However, GenoMELPREDICT performs equally well in Australian families with three or more cases as in European families, where incidence rates are much lower than in Australia. Note also that the GenoMEL dataset includes no Australian families with fewer than three cases, and the predictions of the model for such families in Australia are likely to be inflated.

Genetic testing is not indicated in the following circumstances:

  • Congenital melanomar
  • Melanoma in prepubertal childrenr

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 CDKN2A gene including: 

  • 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

InSight

 CDKN2A – 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  

CDKN2A – risk management

Cancer Council Australia: Clinical practice guidelines for the diagnosis and management of melanoma
Family pathogenic variant not found  

Individual risk estimation taking into account comprehensive risk factors. Patient may still be at very high risk of melanoma and require specialised surveillance. 

Alfred Health – Melanoma risk calculator for health professionals

QIMR Berghofer – Melanoma Risk Predictor

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 3

Date Summary of changes
28/08/2023

Protocol reviewed at October 2022 reference committee meeting. Discussions continued via email and MS Teams. Approved for publication with the following changes made:

  • 2023 cancer genetics genetic testing template changes applied throughout document
  • Target population: addition of sentence "The inclusion of CDKN2A could be considered if panel gene testing is being offered to an individual with pancreatic cancer."
  • Probability of a heritable pathogenic variant: table and figures updated.

Version increased to V.3. Approved on 8/08/2023, published on 28/08/2023. Review in 1 year.

Version 2

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: template sentence added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • Website resources: removed link to European Molecular Genetics Quality Network
  • Version number increased to V.2.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 1

Date Summary of changes
04/10/2019

Protocol presented at May 2019 reference committee meeting. Discussion continued over email. Protocol approved for publication as version V.1. Review in 2 years
19/11/2019 "Unknown significance" changed to "uncertain significance" throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. 

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/1864

10 Sep 2024