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Medulloblastoma panel testing

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  • Individuals diagnosed with medulloblastoma and one or more of the following:
    • SHH molecular subtype diagnosed under age 18 years
    • WNT molecular subtype diagnosed under age 18 years
    • medulloblastoma and multiple adenomatous colorectal polyps
    • medulloblastoma with pigmentary lesions and/or mismatch repair deficient tumour
    • medulloblastoma and a personal history which raises the possibility of Fanconi anaemia (FA).
  • An individual who meets testing criteria for one or more genes included in the panel

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. 

The results of the following investigations may significantly influence the likelihood of detecting a heritable pathogenic variant:

  • somatic testing to determine tumour molecular subtype.

The results of the following investigations may influence the likelihood of detecting a heritable pathogenic variant in one or more of the genes included in the panel:rr

  • Tumour molecular subtype and age show strong association with specific genes (see table)
  • Tumour  histological subtype and age show association with specific genes
    • d​esmoplastic  histology in infancy – SUFU, PTCH1
    • m​edulloblastoma with extensive nodularity (MBEN) in infancy – SUFU, PTCH1
    • large cell/anaplastic histology in childhood – TP53
    • mismatch repair deficient tumour – MLH1, MSH2, MSH6, PMS2, EPCAM
  • Presence of somatic (tumour) CTNNB1 pathogenic variants as APC and CTNNB1 pathogenic variants are mutually exclusive.
Factor Gene Probability of detecting a heritable pathogenic variant
SHH molecular subtype in infancy (under age 3 years)r

SUFU

PTCH1

APC

Any of these 3 genes

11.3%

7.5%

1.3%

20%
SHH molecular subtype in childhood (age 3–18 years)r

TP53

PTCH1

TP53 or PTCH1

14.4%

1.1%

15.5%
WNT molecular subtype in childhood (age 3–18 years)r APC 6.9%
Mismatch repair deficient cancer*

MLH1

MSH2

MSH6

PMS2

EPCAM

 Unknown
Medulloblastoma plus features of FA BRCA2 Unknown

*consider both monoallelic and biallelic pathogenic variants

When choosing genes to include in a gene panel, care should be taken to select genes which have both clinical validity and clinical utility for the phenotype of concern.

The likelihood of identifying a variant of uncertain significance increases as the number of genes included in a panel increases.

Genes associated with medulloblastoma
Gene* Comment
APC International guidelines for risk management of gastrointestinal polyp and cancer risk have been developed; a benefit from screening for medulloblastoma has not been established
BRCA2 Causal link to medulloblastoma not clearly demonstrated. International guidelines for risk management of adult onset cancer risk (e.g. breast and  ovarian cancer) have been developed; expert opinion regarding management of Fanconi anaemia has been published (see www.fanconi.org/explore/clinical-care-guidelines); a benefit from screening for medulloblastoma has not been established
EPCAM​ International guidelines for risk management of adult onset cancer risk (e.g. colorectal and endometrial) have been developed; a benefit from screening for medulloblastoma has not been established
MLH1 International guidelines for risk management of adult onset cancer risk (e.g. colorectal and endometrial) have been developed; a benefit from screening for medulloblastoma has not been established 
MSH2 International guidelines for risk management of adult onset cancer risk (e.g. colorectal and endometrial) have been developed; a benefit from screening for medulloblastoma has not been established
MSH6​ International guidelines for risk management of adult onset cancer risk (e.g. colorectal and endometrial) have been developed; a benefit from screening for medulloblastoma has not been established
PMS2​ International guidelines for risk management of adult onset cancer risk (e.g. colorectal and endometrial) have been developed; a benefit from screening for medulloblastoma has not been established
PTCH1​ Expert recommendations for risk management of Gorlin syndrome have been developed but the optimal screening has not been established; a benefit from screening for medulloblastoma has not been established
SUFU​ Expert recommendations for risk management of Gorlin syndrome due to PTCH1 pathogenic variants have been developed but the optimal screening has not been established; risk management of SUFU pathogenic variants is inferred from PTCH1, a benefit from screening for medulloblastoma has not been established
TP53​ Expert recommendations for risk management have been developed but the optimal screening has not been established; enrolment of pathogenic variant carriers in clinical trial evaluating screening protocols is recommended

 *Genes are listed alphabetically; the order of the listing does not give any indication of the clinical validity/utility of testing the gene

Where a known pathogenic variant is identified in a relative, a pathogenic variant specific test is usually more appropriate and cost effective than a panel test.

In addition to sequencing using genomic sequencing ("next generation sequencing" or NGS), a range of other testing methodologies may be needed to identify pathogenic changes in the genes in the panel including:

  • Sanger sequencing
  • long range PCR
  • copy number analysis (e.g. MLPA)
  • methylation analysis
  • analysis for structural rearrangements (e.g. inversion involving ​MSH2 exon 1–7)

Information about DNA tests and testing laboratories is available from:

Result Reference databases Considerations and advice 
Pathogenic variant search
Pathogenic variant

ClinVar

UMD TP53 Mutation Database

 
Inconclusive 

ClinVar

UMD TP53 Mutation Database

Identify other genes for which a pathogenic variant search could be considered

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).

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Version 3

Date Summary of changes
20/12/2019
  • ‘Unknown significance’ changed to ‘uncertain significance’ throughout document for consistency among eviQ cancer genetics protocols per agreement among the cancer genetics reference committees' chairs. 
  • "Mutation" changed to "pathogenic variant" 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.3.

Version 2

Date  Summary of changes 
18/07/2019

Protocol developed and presented at the February 2019 paediatric cancer genetics reference committee meeting. Discussion continued over email. 

Approved as version V.1. Review in 2 years
28/08/2019 Protocol title changed from 'Panel testing for medulloblastoma' to 'Medulloblastoma panel testing' in accordance with Cancer Genetics Reference Committees' consensus. Version number increased to V.2.

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. Use is subject to eviQ’s disclaimer available at www.eviQ.org.au

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The currency of this information is guaranteed only up until the date of printing, for any updates please check:

https://www.eviq.org.au/p/3654

31 May 2020