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Hereditary Central Nervous System Cancer Panel, Sequencing and Deletion/Duplication

To compare directly to other hereditary cancer panels offered by ARUP Laboratories, see the ARUP Hereditary Cancer Panel Comparison table.

3001633

Hereditary Central Nervous System Cancer Panel, Sequencing and Deletion/Duplication 3001633

Method

Massively Parallel Sequencing/Sequencing/Multiplex Ligation-dependent Probe Amplification

Recommended test to confirm a hereditary cause of CNS cancer in individuals with a personal or family history of CNS cancer
Testing minors for adult-onset conditions is not recommended; testing will not be performed in minors without prior approval.
For additional information, please contact an ARUP genetic counselor at 800-242-2787 ext. 2141.

If a familial sequence variant has been previously identified, targeted sequencing for that variant may be appropriate; refer to the Laboratory Test Directory for additional information.

Pathogenic germline variants in multiple genes have been implicated in hereditary central nervous system (CNS) tumors and cancer. Hereditary cancer predisposition is often characterized by early age of onset (typically before age 50), the presence of any number of CNS tumors in a single individual or closely related family member(s), and variable systemic manifestations. See the Genes Tested table for more details regarding the genes included on this test and associated cancers and syndromes.

Genetics

Genes

Refer to the Genes Tested table for genes included in the panel.

Etiology

Approximately 5% of CNS tumors are associated with a hereditary cause.

Inheritance

Autosomal dominant
Some genes are also associated with autosomal recessive childhood cancer predisposition or other syndromes.

Test Interpretation

Contraindications for Ordering

For individuals with a suspected diagnosis of Lynch syndrome, consider testing specific to Lynch syndrome as some relevant variants are not included on this panel. Refer to Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC) for more information.
Should not be ordered to detect somatic variants associated with malignancy because sensitivity for mosaic variants is low with methodology used for germline assays
Individuals with hematological malignancy and/or a previous allogeneic bone marrow transplant should not undergo molecular genetic testing on peripheral blood specimen.
- Testing of cultured fibroblasts is required for accurate interpretation of test results.

Methodology

This test is performed using the following sequence of steps:

Selected genomic regions, primarily coding exons and exon-intron boundaries, from the targeted genes are isolated from extracted genomic DNA using a probe-based hybrid capture enrichment workflow.
Enriched DNA is sequenced by massively parallel sequencing (MPS; also known as next generation sequencing [NGS]) followed by paired-end read alignment and variant calling using a custom bioinformatics pipeline. The pipeline includes an algorithm for detection of large (single exon-level or larger) deletions and duplications.
Sanger sequencing is performed as necessary to fill in regions of low coverage and in certain situations, to confirm variant calls.
Large deletion/duplication calls made using MPS are confirmed by an orthogonal exon-level microarray when sample quality and technical conditions allow.
Long-range polymerase chain reaction (PCR) followed by nested Sanger sequencing is performed on the following gene and exons:
- PMS2 (NM_000535) 11, 12, 13, 14, 15
Bidirectional Sanger sequencing is performed on the following genes and exons:
- MSH2 (NM_000251) 5
- PMS2 (NM_000535) 7
- PTEN (NM_000314) 9
Multiplex ligation-dependent probe amplification (MLPA) is performed on the following gene to call exon-level deletions and duplications:
- PMS2 (NM_000535)

Sensitivity/Specificity

Clinical Sensitivity

Variable, dependent on phenotype

Analytic Sensitivity/Specificity

Variant Class	Analytic Sensitivity (PPA) Estimate^a (%) and 95% Credibility Region	Analytic Specificity (NPA) Estimate (%)
SNVs	>99 (96.9-99.4)	>99.9
Deletions 1-10 bp^b	93.8 (84.3-98.2)	>99.9
Insertions 1-10 bp^b	94.8 (86.8-98.5)	>99.9
Exon-level^c deletions	97.8 (90.3-99.8) [2 exons or larger] 62.5 (38.3-82.6) [single exon]	>99.9
Exon-level^c duplications	83.3 (56.4-96.4) [3 exons or larger]	>99.9
Exon-level deletions/duplications (MLPA)	>99	>99
^aPPA values are derived from larger methods-based MPS and/or Sanger validations. These values do not apply to testing performed by multiplex ligation-dependent probe amplification (MLPA) unless otherwise indicated. ^bVariants greater than 10 bp may be detected, but the analytic sensitivity may be reduced. ^cIn most cases, a single exon deletion or duplication is less than 450 bp and 3 exons span a genomic region larger than 700 bp. bp, base pairs; NPA, negative percent agreement; PPA, positive percent agreement; SNVs, single nucleotide variants

Limitations

A negative result does not exclude a heritable form of CNS cancer or other cancer.
Diagnostic errors can occur due to rare sequence variations.
Interpretation of this test result may be impacted if this patient has had an allogeneic stem cell transplantation.
The following will not be evaluated:
- Variants outside the coding regions and intron-exon boundaries of targeted gene(s)
- Regulatory region and deep intronic variants
- Breakpoints of large deletions/duplications
- Sequence variants in EPCAM
The following exons are not sequenced due to technical limitations of the assay:
- APC (NM_001354896) exon 12
- APC (NM_001354898, NM_001354904) exon 2
- APC (NM_001354900) exon 11
- MEN1 (NM_001370251) exon 8
- VHL (NM_001354723) exon 2
The following may not be detected:
- Deletions/duplications/insertions of any size by MPS
- Large duplications less than 3 exons in size
- Noncoding transcripts
- Single exon deletions/duplications may not be detected based on the breakpoints of the rearrangement.
- Low-level somatic variants
- Certain other variants due to technical limitations in the presence of pseudogenes and/or repetitive/homologous regions
- Deletions/duplications in the following exons:
  - APC (NM_001354896) 12
  - APC (NM_001354898, NM_001354904) 2
  - APC (NM_001354900) 11
  - MEN1 (NM_001370251) 8
  - PTEN (NM_000314, NM_001304718) 9
  - PTEN (NM_001304717) 1,10
  - RB1 (NM_000321) 22
  - SMARCE1 (NM_003079) 7,10-11
  - VHL (NM_001354723) 2
- The following regions may have reduced sequencing sensitivity due to technical limitations of the assay:
  - RB1 (NM_000321) exon 22
  - SUFU (NM_016169, NM_001178133) exon 1

Genes Tested