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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 a 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.
  • mismatch repair immunohistochemistry.

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 below)
  • 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

TP53

SUFU

PTCH1

APC

ELP1

Less than 1% (none in this cohort)

11.3%

7.5%

1.3%

1.3%r
SHH molecular subtype in infancy (under age 4 years)r GPR161 5.5%
SHH molecular subtype in childhood (age 3–18 years)*r

TP53

SUFU

PTCH1

APC

ELP1

14.4%

Less than 1% (none in this cohort)

1.1%

Less than1% (none in this cohort)

Not reported for this cohort
SHH molecular subtype in childhoodr ELP1

Under age 20 years: 14.4%

Age 3–20 years: 22.4%
SHH molecular subtype in childhood (age 0–18 years)r GPR161 3.4%
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 Fanconi anaemia BRCA2 Unknown

* For all genes except ELP1 the figures for these age ranges were extracted from the supplemental data for Waszak et al. 2018 
** 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
ELP1 Pathogenic variants reported in a single large cohort of SHH paediatric medulloblastoma. No penetrance figures available. 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
GPR161 Pathogenic variants reported in a single large cohort of SHH paediatric medulloblastoma. No penetrance figures available. 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

A variant-specific test (rather than a panel test) 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. 

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:

If these genes are 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.

Result Reference databases Considerations and advice 
Pathogenic variant search
Pathogenic variant

UMD TP53 Mutation Database

LOVD

ClinVar

UMD

HGMD

DMuDB

 
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

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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Bibliography

Farouk Sait, S., M. F. Walsh and M. A. Karajannis 2021. "Genetic syndromes predisposing to pediatric brain tumors." Neurooncol Pract 8(4): 375-390.

The application of high-throughput sequencing approaches including paired tumor/normal sampling with therapeutic intent has demonstrated that 8%-19% of pediatric CNS tumor patients harbor a germline alteration in a classical tumor predisposition gene (NF1, P53). In addition, large-scale germline sequencing studies in unselected cohorts of pediatric neuro-oncology patients have demonstrated novel candidate tumor predisposition genes (ELP1 alterations in sonic hedgehog medulloblastoma). Therefore, the possibility of an underlying tumor predisposition syndrome (TPS) should be considered in all pediatric patients diagnosed with a CNS tumor which carries critical implications including accurate prognostication, selection of optimal therapy, screening, risk reduction, and family planning. The Pediatric Cancer Working Group of the American Association for Cancer Research (AACR) recently published consensus screening recommendations for children with the most common TPS. In this review, we provide an overview of the most relevant as well as recently identified TPS associated with the most frequently encountered pediatric CNS tumors with an emphasis on pathogenesis, genetic testing, clinical features, and treatment implications.

Version 5

Date Summary of changes
30/03/2022

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

Investigations before panel testing

  • 'mismatch repair immunohistochemistry' added

Probability of a heritable pathogenic variant table

  • Row 1: data added for TP53 and ELP1
  • Row 2: added to table
  • Row 3: data added for SUFU, APC and ELP1
  • Row 4 and 5: added to table

Genes that might be included in a medulloblastoma panel

  • ELP1 and GPR161 added to table

Version number increased to V.5. Review in 2 years.

Version 4

Date Summary of changes
20/01/2021

The following sections of the document were updated to align with the new eviQ cancer genetics panel testing template:

  • Related pages: added links to "Guide for health professionals ordering genetic testing" and "Cancer predisposition genes: population carrier frequency". Removed link to "Pre-test counselling"
  • Circumstances in which testing is not indicated: template wording added
  • Testing methods: template wording added
  • Result interpretation: table format updated. Reference databases added. Template sentence added (including link to "Guide for health professionals ordering genetic testing")
  • Counselling: section deleted
  • Website resources: section deleted
  • Version number increased to V.4.
13/10/2021 Protocol title changed from 'Medulloblastoma panel testing' to 'Medulloblastoma – panel testing'.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

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. 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/3654

10 Aug 2022