Invitae Pediatric Nervous System/Brain Tumors Panel

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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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Test description

The Invitae Pediatric Nervous System/Brain Tumors Panel analyzes 24 genes that are associated with an increased risk of developing cancers of the 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 nervous system cancers. Many of these genes are also associated with an increased risk of other cancer types.

Recent studies of cohorts of pediatric cancer patients have reported predisposing gene mutations for several childhood cancers. 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 (24 genes)

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

APC: Deletion/duplication analysis covers the 1A and 1B promoter regions.
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.
TP53: Deletion/duplication analysis covers the promoter region.

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

SDHA: Analysis is limited to sequencing analysis. No clinically-relevant del/dups have been reported.

Advances in genetic testing and studies of cohorts of pediatric cancer patients have reported predisposing gene mutations for several childhood cancers. 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 (an identifiable change in a gene); the remainder are isolated and occur sporadically. Unlike sporadic cases, both hereditary CNS and PNS tumors may be syndromic and associated with extra-CNS features.

There are more than 120 kinds 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 tumor, among others.

Individuals with a pathogenic variant in one of these genes have an increased risk of malignancy compared to the average person, but not everyone with such a variant will actually develop cancer. Further, the same variant can present differently, even among individuals within the same family.

Gene Condition Tumor types PMIDs/references
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
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 schwannoma, 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 rhabdoid tumors, schwannomas 22434719, 24933152, 21208904, 17357086
SMARCE1 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 are associated with hereditary CNS and PNS tumors in an autosomal dominant inheritance pattern. The EPCAM, MLH1, MSH2, MSH6, and PMS2 genes are associated with autosomal recessive constitutional mismatch repair deficiency syndrome (CMMR-D).

Carriers (heterozygotes) of any of the above autosomal recessive conditions have an increased risk for adult-onset cancers. This information will be included in the test report when a result is present.

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)

  1. Asgharian, B, et al. Meningiomas may be a component tumor of multiple endocrine neoplasia type 1. Clin. Cancer Res. 2004; 10(3):869-80. PMID: 14871962
  2. Baysal, BE, Maher, ER. 15 years of paraganglioma: Genetics and mechanism of pheochromocytoma-paraganglioma syndromes characterized by germline SDHB and SDHD mutations. Endocr. Relat. Cancer. 2015; 22(4):T71-82. doi: 10.1530/ERC-15-0226. PMID: 26113606
  3. Benn, DE, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 2006; 91(3):827-36. PMID: 16317055
  4. Berry-Kravis, EM, et al. Congenital central hypoventilation syndrome: PHOX2B mutations and phenotype. Am. J. Respir. Crit. Care Med. 2006; 174(10):1139-44. PMID: 16888290
  5. Bleeker, FE, et al. Brain tumors and syndromes in children. Neuropediatrics. 2014; 45(3):137-61. PMID: 24535705
  6. Bourdeaut, F, et al. ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome. Eur. J. Hum. Genet. 2012; 20(3):291-7. PMID: 22071890
  7. Brugières, L, et al. High frequency of germline SUFU mutations in children with desmoplastic/nodular medulloblastoma younger than 3 years of age. J. Clin. Oncol. 2012; 30(17):2087-93. PMID: 22508808
  8. Brugières, L, et al. Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations. J. Med. Genet. 2010; 47(2):142-4. PMID: 19833601
  9. Chompret, A, et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br. J. Cancer. 2000; 82(12):1932-7. doi: 10.1054/bjoc.2000.1167. PMID: 10864200
  10. Coco, S, et al. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma. J. Hum. Genet. 2012; 57(10):682-4. PMID: 22810114
  11. Cowan, R, et al. The gene for the naevoid basal cell carcinoma syndrome acts as a tumour-suppressor gene in medulloblastoma. Br. J. Cancer. 1997; 76(2):141-5. doi: 10.1038/bjc.1997.354. PMID: 9231911
  12. Diggs-Andrews, KA, et al. Sex Is a major determinant of neuronal dysfunction in neurofibromatosis type 1. Ann. Neurol. 2014; 75(2):309-16. PMID: 24375753
  13. Dow, G, et al. Spinal tumors in neurofibromatosis type 2. Is emerging knowledge of genotype predictive of natural history?. J Neurosurg Spine. 2005; 2(5):574-9. PMID: 15945431
  14. Evans, DG, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J. Med. Genet. 2002; 39(5):311-4. PMID: 12011145
  15. Evans, DG. Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet. Med. 2009; 11(9):599-610. doi: 10.1097/GIM.0b013e3181ac9a27. PMID: 19652604
  16. Gripp, KW, Lin, AE. Costello syndrome: a Ras/mitogen activated protein kinase pathway syndrome (rasopathy) resulting from HRAS germline mutations. Genet. Med. 2012; 14(3):285-92. doi: 10.1038/gim.0b013e31822dd91f. PMID: 22261753
  17. Hamilton, SR, et al. The molecular basis of Turcot's syndrome. N. Engl. J. Med. 1995; 332(13):839-47. doi: 10.1056/NEJM199503303321302. http://ncbi.nlm.nih.gov/pubmed/7661930 PMID: 7661930
  18. Hampel, H, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet. Med. 2015; 17(1):70-87. doi: 10.1038/gim.2014.147. PMID: 25394175
  19. Kerr, B, et al. Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases. J. Med. Genet. 2006; 43(5):401-5. doi: 10.1136/jmg.2005.040352. PMID: 16443854
  20. Knapke, S, et al. Identification, management, and evaluation of children with cancer-predisposition syndromes. Am Soc Clin Oncol Educ Book. 2012; :576-84. PMID: 24451799
  21. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  22. Mody, RJ, et al. Integrative Clinical Sequencing in the Management of Refractory or Relapsed Cancer in Youth. JAMA. 2015; 314(9):913-25. PMID: 26325560
  23. Plon, SE, Nathanson, K. Inherited susceptibility for pediatric cancer. Cancer J. 2005; 11(4):255-67. PMID: 16197716
  24. Raffalli-Ebezant, H, et al. Pediatric intracranial clear cell meningioma associated with a germline mutation of SMARCE1: a novel case. Childs Nerv Syst. 2015; 31(3):441-7. PMID: 25249420
  25. Reilly, KM. Brain tumor susceptibility: the role of genetic factors and uses of mouse models to unravel risk. Brain Pathol. 2009; 19(1):121-31. PMID: 19076777
  26. Riegert-Johnson, DL, et al. Cancer and Lhermitte-Duclos disease are common in Cowden syndrome patients. Hered Cancer Clin Pract. 2010; 8(1):6. PMID: 20565722
  27. Ruijs, MW, et al. TP53 germline mutation testing in 180 families suspected of Li-Fraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J. Med. Genet. 2010; 47(6):421-8. PMID: 20522432
  28. Smith, MJ, et al. Cranial meningiomas in 411 neurofibromatosis type 2 (NF2) patients with proven gene mutations: clear positional effect of mutations, but absence of female severity effect on age at onset. J. Med. Genet. 2011; 48(4):261-5. doi: 10.1136/jmg.2010.085241. PMID: 21278391
  29. Smith, MJ, et al. Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. J. Pathol. 2014; 234(4):436-40. PMID: 25143307
  30. Sredni, ST, Tomita, T. Rhabdoid tumor predisposition syndrome. Pediatr. Dev. Pathol. 2015; 18(1):49-58. doi: 10.2350/14-07-1531-MISC.1. PMID: 25494491
  31. Stratakis, CA, et al. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J. Clin. Endocrinol. Metab. 2001; 86(9):4041-6. PMID: 11549623
  32. Taylor, MD, et al. Mutations in SUFU predispose to medulloblastoma. Nat. Genet. 2002; 31(3):306-10. PMID: 12068298
  33. Thomas, M, et al. Metastatic medulloblastoma in an adolescent with Simpson-Golabi-Behmel syndrome. Am. J. Med. Genet. A. 2012; 158A(10):2534-6. PMID: 22893378
  34. Torres, OA, et al. Early diagnosis of subependymal giant cell astrocytoma in patients with tuberous sclerosis. J. Child Neurol. 1998; 13(4):173-7. PMID: 9568761
  35. Trochet, D, et al. PHOX2B genotype allows for prediction of tumor risk in congenital central hypoventilation syndrome. Am. J. Hum. Genet. 2005; 76(3):421-6. PMID: 15657873
  36. Walker, L, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br. J. Cancer. 2006; 95(2):233-8. doi: 10.1038/sj.bjc.6603227. PMID: 16786042
  37. Wilkie, AO. New germline syndrome with brainstem abnormalities and neuroblastoma, caused by ALK mutation. Hum. Mutat. 2011; 32(3):v. PMID: 21972113
  38. Wimmer, K, et al. Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium 'care for CMMRD' (C4CMMRD). J. Med. Genet. 2014; 51(6):355-65. doi: 10.1136/jmedgenet-2014-102284. PMID: 24737826
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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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALK NM_004304.4
APC* NM_000038.5
DICER1 NM_177438.2
EPCAM* NM_002354.2
HRAS NM_005343.2
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: Deletion/duplication analysis covers the 1A and 1B promoter regions.
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.