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  • Test code: 01106
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
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Invitae Pediatric Nervous System/Brain Tumors Panel

Test description

The Invitae Pediatric Nervous System/Brain Tumors Panel analyzes genes associated with an increased risk of developing tumors of the brain and central and peripheral nervous systems in childhood or adolescence. These genes were selected based on the available evidence to date to provide Invitae’s most comprehensive panel for hereditary pediatric brain and nervous system tumors. Many of these genes are also associated with an increased risk of other cancer types.

Recent studies of pediatric cancer patients have reported predisposing pathogenic variants in a number of heritable genes. The results show that approximately 10% of children who develop cancer have an underlying cancer-predisposing condition. Genetic testing of these genes may confirm a diagnosis and can substantially influence the choice of appropriate screening and medical management options for the child and other relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.

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Primary panel (26 genes)

AIP ALK APC DICER1 EPCAM HRAS LZTR1 MEN1 MLH1 MSH2 MSH6 NF1 NF2 PHOX2B PMS2 PRKAR1A PTCH1 PTEN RB1 SMARCB1 SMARCE1 SUFU TP53 TSC1 TSC2 VHL

Add-on Hereditary Paraganglioma-Pheochromocytoma Genes (8 genes)

Head-and-neck paragangliomas are neuroendocrine tumors that may occur in families with hereditary paraganglioma pheochromocytoma (PGL-PCC) syndrome. Clinicians can choose to include eight genes that are associated with PGL-PCC at no additional charge.

MAX RET SDHA SDHAF2 SDHB SDHC SDHD TMEM127

Advances in genetic testing and studies of pediatric cancer patients have reported predisposing pathogenic genetic variants in a number of heritable genes. Identification of a hereditary cancer predisposition in childhood or adolescence can substantially influence the choice of appropriate screening and medical management options for the child and other relatives.

Although brain tumors are rare in the general population, they are the most common form of solid tumors among children under the age of 15, representing approximately 20% of all childhood cancers. Central nervous system (CNS) tumors are the most common cancers among children ages 0–19 years. Peripheral nervous system (PNS) tumors are rare in adults and children. Approximately 5%–10% of CNS tumors are hereditary and due to a pathogenic variant; the remainder are isolated and occur sporadically. Unlike sporadic cases, both hereditary CNS and PNS tumors may be syndromic and associated with features outside of the nervous system.

There are more than 120 types of nervous system tumors, including astrocytomas, atypical teratoid rhabdoid tumor (AT/RT), chondrosarcoma, choroid plexus, craniopharyngioma, ependymoma, germ cell tumor, glioblastoma, glioma, medulloblastoma, hemangioblastoma, meningioma, neurofibroma, schwannoma and malignant peripheral nerve sheath tumors, among others.

Individuals with a pathogenic variant in one of these genes have an increased risk to develop pediatric solid tumors of the brain and nervous system compared to the average person, but not everyone with such a variant will actually develop a tumor. Further, the same variant may manifest with different symptoms, even among family members. Because we cannot predict which tumors may develop, additional medical management strategies focused on cancer prevention and early detection may be beneficial. For gene-associated risks, see the tables below.

Gene Condition Tumor types PMIDs/references
AIP Familial isolated pituitary adenoma (FIPA) Pituitary adenoma 23371967, 22720333
ALK Familial neuroblastoma neuroblastoma 18724359, 18923523, 22071890, 18923503
APC Familial adenomatous polyposis (FAP) medulloblastoma 7661930
DICER1 DICER1 syndrome pituitary blastoma, pineoblastoma 25022261, 24839956
EPCAM Constitutional mismatch repair deficiency (CMMR-D) high-grade glioma, supratentorial primitive neuroectodermal tumors (PNET) 24737826, 24535705
HRAS Costello syndrome neuroblastoma 16443854, 22261753
LZTR1 Schwannomatosis schwannoma 25480913, 24362817, 25335493
MEN1 Multiple endocrine neoplasia type 1 (MEN1) meningiomas, spinal ependymomas, schwannomas 14871962
MLH1 Constitutional mismatch repair deficiency (CMMR-D) high-grade glioma, supratentorial PNET 24535705, 24440087, 24737826, 24556086
MSH2 Constitutional mismatch repair deficiency (CMMR-D) high-grade glioma, supratentorial PNET 24535705, 24440087, 24737826, 24556086
MSH6 Constitutional mismatch repair deficiency (CMMR-D) high-grade glioma, supratentorial PNET 24535705, 24440087, 24737826, 24556086
NF1 Neurofibromatosis type 1 pheochromocytoma, optic glioma, neurofibromas, other CNS malignancies 24535705
NF2 Neurofibromatosis type 2 vestibular schwannoma, spinal schwannoma, meningioma 24535705, 19652604
PHOX2B Familial neuroblastoma neuroblastoma, ganglioneuroma, ganglioneuroblastoma 16888290, 15657873
PMS2 Constitutional mismatch repair deficiency (CMMR-D) high-grade glioma, supratentorial PNET 24535705, 24440087, 24737826, 24556086
PRKAR1A Carney complex psammomatous melanotic schwannoma 11549623
PTCH1 Basal cell nevus syndrome (Gorlin syndrome) medulloblastoma 9231911
PTEN PTEN hamartoma syndrome Lhermitte-Duclos (dysplastic gangliocytoma of the cerebellum) 20565722
RB1 Familial retinoblastoma retinoblastoma 20301625, 8304343
SMARCB1 Rhabdoid tumor predisposition syndrome, schwannomatosis rhabdoid tumors, schwannomas 22434719, 24933152, 21208904, 17357086
SMARCE1 Familial meningioma clear cell meningioma 25249420, 25143307
SUFU Basal cell nevus syndrome (Gorlin syndrome) medulloblastoma 22508808, 19833601,12068298
TP53 Li-Fraumeni syndrome astrocytomas, glioblastomas, medulloblastomas, choroid plexus carcinoma 10864200, 20522432, 24535705
TSC1 Tuberous sclerosis subependymal giant cell astrocytomas 9568761
TSC2 Tuberous sclerosis subependymal giant cell astrocytomas 9568761
VHL von Hippel Lindau syndrome hemangioblastoma 21955200

The majority of genes on this panel have an autosomal dominant hereditary predisposition to CNS and PNS tumors. The MLH1, MSH2, MSH6, and PMS2 genes are associated with autosomal recessive constitutional mismatch repair deficiency syndrome (CMMR-D).

Carriers of CMMR-D have an increased risk for adult-onset Lynch syndrome. This information will be included in the test report, when such variants are identified.

The Invitae Pediatric Nervous System/Brain Tumors Panel may be considered for children or young adults with the types of nervous system/brain tumors listed above or whose personal or family history is suggestive of a hereditary nervous system tumor predisposition syndrome, including:

  • a brain tumor diagnosed under the age of 18
  • a brain tumor and:
    • hypopigmented skin lesions
    • consanguineous parents (parents who are related by blood)
    • a personal or family history of cancers or features associated with Lynch syndrome, Li-Fraumeni syndrome, tuberous sclerosis complex, neurofibromatosis type 1 (NF1), or basal cell nevus (Gorlin) syndrome
    • a second primary cancer
    • a sibling with a childhood cancer
  • an astrocytoma and melanoma
  • two first-degree relatives with an astrocytoma and melanoma
  • a medulloblastoma and ≥10 cumulative adenomatous colon polyps

There are also some common, general features suggestive of a hereditary cancer syndrome family. These include:

  • cancer diagnosed at an unusually young age
  • different types of cancer that have occurred independently in the same person
  • cancer that has developed in both of a set of paired organs (e.g., both kidneys, both breasts)
  • several close blood relatives that have the same type of cancer
  • unusual cases of a specific cancer type (e.g., breast cancer in a man)

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Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
AIP NM_003977.3
ALK NM_004304.4
APC* NM_000038.5
DICER1 NM_177438.2
EPCAM* NM_002354.2
HRAS NM_005343.2
LZTR1 NM_006767.3
MAX NM_002382.4
MEN1 NM_130799.2
MLH1* NM_000249.3
MSH2* NM_000251.2
MSH6 NM_000179.2
NF1 NM_000267.3
NF2 NM_000268.3
PHOX2B* NM_003924.3
PMS2 NM_000535.5
PRKAR1A NM_002734.4
PTCH1 NM_000264.3
PTEN* NM_000314.4
RB1 NM_000321.2
RET NM_020975.4
SDHA* NM_004168.3
SDHAF2 NM_017841.2
SDHB NM_003000.2
SDHC NM_003001.3
SDHD NM_003002.3
SMARCB1 NM_003073.3
SMARCE1 NM_003079.4
SUFU NM_016169.3
TMEM127 NM_017849.3
TP53* NM_000546.5
TSC1 NM_000368.4
TSC2 NM_000548.3
VHL NM_000551.3

APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.
EPCAM: Analysis is limited to deletion/duplication analysis.
MLH1: Deletion/duplication analysis covers the promoter region.
MSH2: Analysis includes the exon 1-7 inversion (Boland mutation).
PHOX2B: Alanine repeat numbers for the commonly expanded region in exon 3 are not determined.
PTEN: Deletion/duplication analysis covers the promoter region.
SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.
TP53: Deletion/duplication analysis covers the promoter region.