Invitae Nervous System/Brain Cancer Panel


Test description

The Invitae Nervous System/Brain Cancer Panel analyzes up to 40 genes that are associated with an increased lifetime risk of developing cancers of the central and peripheral nervous systems. These genes were selected based on the available evidence to date to provide Invitae’s most comprehensive hereditary nervous system cancers panel. Many of these genes are also associated with an increased risk of other cancer types.

Genetic testing of these genes may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk 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 (25 genes)


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 preliminary-evidence genes (7 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.


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.


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

  • Carney complex
  • Constitutional mismatch repair deficiency syndrome (CMMR-D)
  • Cowden syndrome
  • Familial adenomatous polyposis (FAP)
  • Familial neuroblastoma
  • Li-Fraumeni syndrome (LFS)
  • Nevoid basal cell carcinoma (NBCS)—also known as Gorlin syndrome
  • Neurofibromatosis type 1 (NF1)
  • Neurofibromatosis type 2 (NF2)
  • Retinoblastoma
  • Rhabdoid tumor predisposition syndrome
  • Simpson-Golabi-Behmel syndrome (SGBS1)
  • Tuberous sclerosis complex (TSC)
  • von Hippel-Lindau syndrome (VHL)

The nervous system is a complex network of nerves and cells that carry messages to and from the brain and spinal cord to various parts of the body. The nervous system includes both the central nervous system (CNS) and peripheral nervous system (PNS). The CNS is composed of the brain and spinal cord; the PNS consists of the somatic and autonomic nervous systems.

A tumor can form within the cells and tissues that comprise the nervous system, resulting in uncontrolled growth and the formation of a mass. These abnormal growths may be malignant or benign, can form in different areas of the nervous system throughout the body, could develop from different cell types, and may have different treatment options.

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.

The general population risk for developing a CNS tumor is between 0.55%–0.69%. PNS tumors are rare in adults and children; CNS tumors are the most common cancers among children ages 0-19. Approximately 5% 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.

If a pathogenic variant is identified, this means there is an increased risk of malignancy compared to the average person, but not everyone with such a variant will develop cancer. Further, the same variant can cause different cancers, even among individuals within the same family. Because we cannot predict which cancers may develop, most people who are found to have a pathogenic variant will be offered various screening tests to detect and prevent cancer. For gene-associated cancer risks, see the table below.

GeneCNS tumor typeRiskPNS tumor typeRisk
ALK neuroblastoma, medulloblastoma elevated (PMID: 22810114, _ _
22071890, 21972113)
APC medulloblastoma 1%–2% (PMID: 7661930) _ _
DICER1 pituitary blastoma, pineoblastoma elevated (PMID: 25022261, 24839956) _ _
EPCAM high-grade glioma, supratentorial PNET 35% (PMID: 24737826, 24535705) _ _
HRAS _ _ neuroblastoma elevated (PMID: 16443854, 22261753)
MEN1 meningiomas, spinal ependymomas, schwannomas elevated risk (PMID: 14871962) _ _
MLH1 high-grade glioma, supratentorial primitive neuroectodermal tumors (PNET) 35% (PMID: 24737826, 24535705) _ _
MSH2 high-grade glioma, supratentorial PNET 35% (PMID: 24737826, 24535705) _ _
MSH6 high-grade glioma, supratentorial PNET 55% (PMID: 24737826, 24535705) _ _
NF1   optic glioma, other CNS malignancies 15% (PMID: 24535705) malignant peripheral nerve sheath tumors, pheochromocytoma 10% (PMID: 24535705)
NF2 meningiomas, spinal tumors 50%–75% (PMID: 24535705) 66% (PMID: 24535705) bilateral vestibular schwannoma ~100% (PMID: 19652604)
PHOX2B neuroblastoma, ganglioneuroma, ganglioneuroblastoma 5%–6% (PMID: 16888290, 15657873) _ _
PMS2 high-grade glioma, supratentorial PNET 60% (PMID: 24737826, 24535705) _ _
PRKAR1A _ _ psammomatous melanotic schwannoma 10% (PMID:11549623)
PTCH1 medulloblastoma 5% (PMID: 9231911) _ _
PTEN Lhermitte-Duclos (dysplastic gangliocytoma of the cerebellum) up to 32% (PMID: 20565722) _ _
RB1 Retinoblastoma nearly 100% (PMID: 20301625, 8304343) _ _
SMARCA4 atypical teratoid/rhabdoid tumor (AT/RT), schwannoma unknown (PMID: 25494491, 24535705) schwannoma unknown (PMID: 24535705)
SMARCB1 atypical teratoid/rhabdoid tumor (AT/RT), schwannoma elevated (PMID: 25494491, 24535705) schwannoma elevated (PMID: 24535705)
SMARCE1 clear cell meningioma unknown (PMID: 25249420, 25143307) _ _
SUFU medulloblastoma elevated (PMID: 22508808, 19833601,12068298) _ _
TP53 astrocytomas, glioblastomas, medulloblastomas, choroid plexus carcinoma elevated (PMID: 10864200, 20522432, 24535705) _ _
TSC1 subependymal giant cell astrocytomas 6%–14% (PMID: 9568761) _ _
TSC2 subependymal giant cell astrocytomas 6%–14% (PMID: 9568761) _ _
VHL   hemangioblastoma 60%–80% (PMID: 21955200) _ _

Elevated: There is evidence of association, but the penetrance and risk are not well characterized.
Unknown: Based on small studies, the risk is possibly increased, though not well-described.

The 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 also associated with autosomal recessive constitutional mismatch repair deficiency syndrome (CMMR-D).

This panel may be considered for individuals whose personal and/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 and/or family history of cancers and/or features associated with Lynch syndrome, Li-Fraumeni syndrome, tuberous sclerosis neurofibromatosis type 1, or Gorlin syndrome
  • a second primary cancer
  • a sibling with a childhood cancer
  • an astrocytoma and melanoma in the same person or in two first-degree relatives
  • a medulloblastoma and ≥10 cumulative adenomatous colon polyps in the same person

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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  2. American Cancer Society, Lifetime Risks of Developing or Dying from Cancer, Accessed August 2015.
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  4. 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
  5. Benn, DE, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 2006; 91(3):827-36. PMID: 16317055
  6. 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
  7. Bleeker, FE, et al. Brain tumors and syndromes in children. Neuropediatrics. 2014; 45(3):137-61. PMID: 24535705
  8. 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
  9. 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
  10. 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
  11. 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
  12. Coco, S, et al. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma. J. Hum. Genet. 2012; 57(10):682-4. PMID: 22810114
  13. 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
  14. 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
  15. 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
  16. Evans, DG, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J. Med. Genet. 2002; 39(5):311-4. PMID: 12011145
  17. 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
  18. 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
  19. Hamilton, SR, et al. The molecular basis of Turcot's syndrome. N. Engl. J. Med. 1995; 332(13):839-47. doi: 10.1056/NEJM199503303321302. PMID: 7661930
  20. 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
  21. 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
  22. Lohmann, DR, Gallie, BL. Retinoblastoma. 2000 Jul 18. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301625
  23. Martins, R, Bugalho, MJ. Paragangliomas/Pheochromocytomas: clinically oriented genetic testing. Int J Endocrinol. 2014; 2014:794187. doi: 10.1155/2014/794187. PMID: 24899893
  24. National Brain Tumor Society. Understanding brain tumors: Accessed August 2015.
  25. Naumova, A, Sapienza, C. The genetics of retinoblastoma, revisited. Am. J. Hum. Genet. 1994; 54(2):264-73. PMID: 8304343
  26. 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
  27. 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
  28. 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
  29. 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
  30. 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
  31. 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
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  33. 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
  34. Taylor, MD, et al. Mutations in SUFU predispose to medulloblastoma. Nat. Genet. 2002; 31(3):306-10. PMID: 12068298
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  36. 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
  37. 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
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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
BAP1 NM_004656.3
BARD1 NM_000465.3
DICER1 NM_177438.2
EPCAM* NM_002354.2
EZH2 NM_004456.4
GPC3 NM_004484.3
HRAS NM_005343.2
KIF1B NM_015074.3
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
POT1 NM_015450.2
PRKAR1A NM_002734.4
PTCH1 NM_000264.3
PTCH2 NM_003738.4
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
SMARCA4 NM_001128849.1
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.