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Rhabdoid tumour predisposition syndrome – panel testing

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  • Individuals diagnosed with an intracranial rhabdoid tumour (atypical teratoid/rhabdoid tumour) or extracranial malignant rhabdoid tumour (MRT) at any age.
  • SMARCA4-deficient tumour (any histology).
    • Currently there is no evidence that SMARCB1-deficient tumours other than MRT necessitate genetic testing, but it could be considered on a research basis.r

Note

In the following settings a variant-specific test (rather than sequencing a single gene or gene panel) may be more appropriate and cost effective:

  • Where a known germline pathogenic variant has been identified in a relative.
  • Where a specific pathogenic variant has been identified on somatic tumour testing.

Genetic testing is important for good clinical care of individuals who are suspected of having a familial cancer/tumour predisposition.

If a child or young person (CYP) falls outside the target group but the CYP has been diagnosed with two or more primary tumours/cancers, or has a significant family history of cancer, or has other features that raise the possibility of a cancer predisposition syndrome, referral to a clinical genetics service for additional phenotyping and consideration of broader genomic testing is recommended. See Paediatric cancer and tumours – referring to genetics

The results of the following investigations may influence the likelihood of detecting a heritable pathogenic variant in the SMARCB1 or SMARCA4 genes:

  • verification and/or review of relevant histopathology
  • tumour testing that identifies one or more of:
    • a somatic SMARCB1 or SMARCA4 variant
    • loss of SMARCB1 (also called INI1 or BAF47) or SMARCA4 (also called BRG1) protein expression on immunohistochemistry.

Up to 35% of individuals with a malignant rhabdoid tumour (MRT) have a heritable pathogenic SMARCB1 variant.r These individuals have Rhabdoid Tumour Predisposition Syndrome 1 (RTPS1). Germline SMARCB1 variants are usually de novo, and germline mosaicism has been reported.r

Much more rarely, individuals with an MRT have a heritable pathogenic SMARCA4 variant (the proportion is yet to be clarified). These individuals have Rhabdoid Tumour Predisposition Syndrome 2 (RTPS2). SMARCA4 variants are often inherited from an unaffected parent.r

SMARCB1 and SMARCA4 pathogenic variants that cause RTPS are predominantly truncating.

Factor Probability of detecting a heritable SMARCB1 pathogenic variant
Individuals with single site MRT at any age Up to 35%r
Individuals diagnosed with single site MRT over age 1 year  Approximately 10%r
Individuals with multiple MRTs Close to 100%r
Individuals with congenital MRTs At least 66%r
Factor Probability of detecting a heritable SMARCA4 pathogenic variant
Individuals with small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT) At least 40%r
Individuals with SCCOHT diagnosed under age 15 years Up to 100%r

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 rhabdoid tumour predisposition syndrome
Gene^ Comment
SMARCA4
SMARCB1

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

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

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
  • 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 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 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

SMARCA4-associated rhabdoid tumour predisposition syndrome – risk management

SMARCB1-associated rhabdoid tumour predisposition syndrome – 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

# The type of variant should be taken into account – RTPS is usually associated with truncating variants, while other conditions, including schwannomatosis and Coffin-Siris syndrome, are usually associated with missense variants.r

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
04/07/2023

Document reviewed at paediatric cancer genetics reference committee meeting on 23 June 2022. Discussions continued electronically via email and MS Teams. Approved fpr publication with the following changes made: 

  • 2023 cancer genetics panel testing template changes applied throughout document
  • Target population: section revised
  • Investigations before panel testing: minor wording changes
  • Probability of a heritable pathogenic variant: 
    • Introductory paragraph revised
    • Figures in the table revised
    • "SCCOHT diagnosed under age 15 years" added to the table
  • Genes that might be included in a rhabdoid tumour predisposition syndrome panel: minor wording changes in the table
  • Result interpretation: footnote to the table added

Version increased to V.3. Approved for publishing on 04/07/2023. Review in 2 years

Version 2

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 link to "Guide for health professionals ordering genetic testing". 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 database 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.2.
11/10/2021 Protocol title changed from 'Rhabdoid tumour predisposition syndrome panel testing' to 'Rhabdoid tumour predisposition syndrome – panel testing'.
10/11/2021 Removed link to "European Directory of DNA Diagnostic Laboratories"

Version 1

Date Summary of changes
6/07/2020 New protocol developed and discussed by the cancer genetics paediatric reference committee at the July 2019 reference committee meeting. Protocol approved for publication as V.1. Review in 1 year.

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/3741

10 Sep 2024