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  • Test code: 01104
  • 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 Solid Tumors Panel

Test description

The Invitae Pediatric Solid Tumors Panel analyzes 52 genes associated with a hereditary predisposition to the development of pediatric solid tumors. These genes were selected based on the available evidence to date to provide Invitae’s most comprehensive panel for pediatric solid tumors. Some 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 (53 genes)

AIP ALK APC AXIN2 BAP1 BLM BMPR1A CDC73 CDKN1C DICER1 DIS3L2 EPCAM EXT1 EXT2 FH GPC3 HRAS LZTR1 MAX MEN1 MLH1 MSH2 MSH6 NBN NF1 NF2 PHOX2B PMS2 PRKAR1A PTCH1 PTEN RB1 RECQL4 REST RET SDHA SDHAF2 SDHB SDHC SDHD SMAD4 SMARCA4 SMARCB1 SMARCE1 STK11 SUFU TMEM127 TP53 TSC1 TSC2 VHL WRN WT1

Advances in genetic testing and studies of pediatric cancer patients have reported predisposing pathogenic 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.

Solid tumors comprise approximately 30% of all pediatric cancers. Pediatric solid tumors include carcinomas and sarcomas that can develop nearly anywhere in the body. The most common types of brain tumors include neuroblastoma, rhabdomyosarcoma, Wilms tumor, and osteosarcoma.

Recent studies suggest that approximately 10% of all pediatric cancers are due to an underlying germline pathogenic variant. Zhang et al., 2015 identified pathogenic variants in cancer-related genes among a significant proportion of individuals with pediatric solid tumors (16.7% of those with non-central nervous system solid tumors and 8.6% of those with central nervous system solid tumors) (PMID: 26580448). This suggests utility in evaluating this population for hereditary cancer conditions. Results may allow for condition-specific medical management and surveillance, provide recurrence risk assessment, and guide family planning.

Individuals with a pathogenic variant in one of these genes have an increased risk to develop pediatric solid tumors 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.

Major tumor subtypes included in this test

Tumor type Genes
Colorectal AXIN2, APC, BLM, BMPR1A, EPCAM, MLH1, MSH2, MSH6, PMS2, PTEN, SMAD4, STK11, TP53
Meningioma NF2, SMARCE1, MEN1, WRN
Neuroblastoma ALK, HRAS, PHOX2B
Nevus basal cell carcinoma and medulloblastoma PTCH1, SUFU
Osteochondroma, osteochondrosarcoma EXT1, EXT2
Paraganglioma/ Pheochromocytoma (PGL/PCC) MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, TMEM127, VHL
Pituitary adenoma AIP
Renal (including Wilms tumor) BAP1, CDC73, CDKN1C, DIS3L2, FH, GPC3, REST, SDHAF2, SDHB, SDHC, SDHD, TMEM127, TSC1, TSC2, VHL, WT1
Rhabdoid tumor and small-cell carcinoma of the ovary, hypercalcemic type SMARCB1, SMARCA4
Rhabdomyosarcoma and (other sarcomas) DICER1, EPCAM, MLH1, MSH2, MSH6, PMS2, HRAS, NBN, (APC, BLM, FH, RB1, RECQL4, TP53, WRN
Schwannoma SMARCB1, LZTR1

Conditions and tumor types by gene

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) colon, thyroid, hepatoblastoma, sarcoma 8150351, 18063416, 19822006, 1673441, 3036290, 7698732
AXIN2 Oligodontia-colorectal cancer syndrome colorectal 21416598, 26025668, 15042511
BAP1 BAP1 hereditary cancer predisposition syndrome renal cell carcinoma, uveal melanoma, mesothelioma 26096145
BLM Bloom syndrome connective tissue carcinoma, sarcoma Bloom’s syndrome registry: http://weill.cornell.edu/bsr/data_from_registry/
BMPR1A Juvenile polyposis syndrome colorectal, gastric, pancreatic, juvenile GI polyps 25645574, 16246179, 17303595, 20859198, 9869523
CDC73 CDC73-related conditions parathyroid carcinoma, ossifying jaw fibromas, benign renal tumors 20301744, 15606373
CDKN1C Beckwith-Wiedemann syndrome Wilms tumor, hepatoblastoma, rhabdomyosarcoma 16010495, 12138139
DICER1 DICER1 syndrome pleuropulmonary blastoma and cystic nephroma, rhabdomyosarcoma, pituitary blastoma, pineoblastoma 24839956, 22180160, 21266384
DIS3L2 Perlman syndrome Wilms tumor 18780370, 23613427, 22306653
EPCAM Constitutional mismatch repair deficiency (CMMR-D) brain and nervous system, colorectal, rhabdomyosarcoma 24440087, 24737826, 24556086
EXT1, EXT2 Hereditary multiple osteochondromas (HMO) Osteochondroma, osteochondrosarcoma 19810120, 18853760, 24532482, 13754517, 1856833, 8027127
FH Hereditary leiomyomatosis, renal cell cancer (HLRCC); autosomal recessive fumarase deficiency renal cell carcinoma, uterine leiomyosarcoma 25012257, 20301430, 25018647, 16477632
GPC3 Simpson-Golabi-Behmel syndrome Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma 16010678, 16010678, 25238977, 23606591, 20301398
HRAS Costello syndrome rhabdomyosarcoma, neuroblastoma 11857556, 20301680, 22261753
LZTR1 Schwannomatosis schwannoma 25480913, 24362817, 25335493
MAX Hereditary paraganglioma-pheochromocytoma syndrome (PGL/PCC) paraganglioma, pheochromocytoma 24523625, 26347711, 22452945
MEN1 Multiple endocrine neoplasia type 1 (MEN1) parathyroid adenoma, anterior pituitary, thyroid (including goiter), adrenocortical carcinoma, meningioma 23933118, 11836268, 22084155, 19904212
MLH1 Constitutional mismatch repair deficiency (CMMR-D) brain and nervous system, colorectal, rhabdomyosarcoma 24440087, 24737826, 24556086
MSH2 Constitutional mismatch repair deficiency (CMMR-D) brain and nervous system, colorectal, rhabdomyosarcoma 24440087, 24737826, 24556086
MSH6 Constitutional mismatch repair deficiency (CMMR-D) brain and nervous system, colorectal, rhabdomyosarcoma 24440087, 24737826, 24556086
NBN Nijmegen breakage syndrome (NBS) medulloblastomas, gliomas, rhabdomyosarcomas 15474156
NF1 Neurofibromatosis type 1 (NF1) schwannoma, pheochromocytoma, optic glioma, neurofibromas 25130111, 20833335, 24535705
NF2 Neurofibromatosis type 2 (NF2) vestibular schwannoma, spinal schwannoma, meningioma 19652604, 21278391, 15945431
PHOXB2 neuroblastoma 25124476, 25435121
PMS2 Constitutional mismatch repair deficiency (CMMR-D) brain and nervous system, colorectal, rhabdomyosarcoma 24440087, 24737826, 24556086
PRKAR1A Carney complex nerve sheath, thyroid, sarcoma, large-cell calcifying Sertoli cell 26130139, 16756677, 20301463
PTCH1 Basal cell nevus syndrome (Gorlin syndrome) basal cell carcinoma, medulloblastoma 26409035, 20301330
PTEN PTEN hamartoma syndrome thyroid, colon 22252256
RB1 Familial retinoblastoma retinoblastoma, sarcoma, melanoma 22355046, 20301625, 8304343
RECQL4 Rothmund-Thomson syndrome, Baller-Gerold syndrome, RAPADILINO syndrome osteosarcoma, basal cell carcinoma, squamous cell carcinoma 11471165, 12952869
REST Wilms Tumor 26551668, 9771705
RET Multiple endocrine neoplasia type 2 medullary thyroid carcinoma, pheochromocytoma 20301434, 21862994
SDHA Hereditary PGL/PCC; mitochondrial complex II deficiency paraganglioma, pheochromocytoma, gastrointestinal stromal 23612575, 17804857, 24096523, 26113606, 20301715, 24523625
SDHAF2 Hereditary PGL/PCC paraganglioma, pheochromocytoma, gastrointestinal stromal, renal, thyroid 20301715, 24523625
SDHB Hereditary PGL/PCC; mitochondrial complex II deficiency paraganglioma, pheochromocytoma, gastrointestinal stromal, renal, thyroid 17667967, 17804857, 24096523, 26113606, 26347711, 20301715, 24523625
SDHC Hereditary PGL/PCC paraganglioma, pheochromocytoma, gastrointestinal stromal, renal, thyroid 17667967, 17804857, 21173220, 24903423, 20301715, 24523625
SDHD Hereditary PGL/PCC paraganglioma, pheochromocytoma, gastrointestinal stromal, renal, thyroid 17667967, 17804857, 16317055, 20301715, 24523625
SMARCA4 small-cell carcinoma of the ovary, hypercalcemic type 26975901, 27100627
SMAD4 Juvenile polyposis syndrome colorectal, gastric, pancreatic, juvenile GI polyps 20301642, 25645574, 17303595, 16246179, 9869523
SMARCB1 Rhabdoid tumor predisposition syndrome, schwannomatosis rhabdoid, schwannomas 22434719, 24933152, 21208904, 17357086
SMARCE1 Familial meningioma clear cell meningioma 25249420, 25143307
STK11 Peutz-Jeghers syndrome colorectal, gastric, pancreatic, duodenal, lung 20051941, 20581245, 25645574
SUFU Basal cell nevus syndrome (Gorlin syndrome) basal cell carcinoma, medulloblastoma 22508808, 19833601, 12068298, 20301330, 25403219
TMEM127 Hereditary PGL/PCC paraganglioma, pheochromocytoma, gastrointestinal stromal, renal, thyroid 24899893, 26347711
TP53 Li-Fraumeni syndrome adrenocortical carcinoma, choroid plexus carcinoma, sarcomas, brain/nervous system, colorectal, many others 10864200, 20522432, 20301488
TSC1 Tuberous sclerosis brain/nervous system, renal 21182496, 9568761
TSC2 Tuberous sclerosis brain and nervous system, renal 21182496, 9568761
VHL von Hippel Lindau syndrome hemangioblastoma, renal cell carcinoma, pancreatic neuroendocrine (PNET), pheochromocytoma, epididymal 21386872, 25611110, 21955200, 26279462, 24899893
WRN Werner syndrome soft-tissue sarcoma, osteosarcoma, melanoma, thyroid carcinoma, meningioma 20301687, 23573208, 14676353
WT1 WT1-related disorders (Denys-Drash, WAGR, Frasier syndrome) Wilms tumor 12193442, 25688735, 8827067, 25623218, 20301471, 15150775

Most of the genes on this panel have autosomal dominant inheritance. GPC3 is associated with X-linked Simpson-Golabi-Behmel syndrome. Several other genes have autosomal recessive inheritance, or result in clinically distinct autosomal recessive conditions, as outlined below:

  • The MLH1, MSH2, MSH6 and PMS2 genes are associated with constitutional mismatch repair deficiency (CMMR-D)
  • FH is associated with fumarate hydratase deficiency
  • BLM is associated with Bloom syndrome
  • NBN is associated with Nijmegen breakage syndrome
  • SDHA and SDHB are associated with mitochondrial complex II deficiency syndrome

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.

This panel may be considered for children or young adults with the types of solid tumors listed above. Other candidates for testing include those whose clinical or family history is suggestive of a hereditary cancer syndrome.

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. Evans, DG, Farndon, PA. Nevoid Basal Cell Carcinoma Syndrome. 2002 Jun 20. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1151/ PMID: 20301330
  2. Lammi, L, et al. Mutations in AXIN2 cause familial tooth agenesis and predispose to colorectal cancer. Am. J. Hum. Genet. 2004; 74(5):1043-50. doi: 10.1086/386293. PMID: 15042511
  3. Petersen, GM, et al. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991; 100(6):1658-64. PMID: 1673441
  4. Falchetti, A, et al. Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors. Genet. Med. 2009; 11(12):825-35. doi: 10.1097/GIM.0b013e3181be5c97. PMID: 19904212
  5. Brosens, LA, et al. Risk of colorectal cancer in juvenile polyposis. Gut. 2007; 56(7):965-7. doi: 10.1136/gut.2006.116913. PMID: 17303595
  6. Pithukpakorn, M, Toro, JR. Hereditary Leiomyomatosis and Renal Cell Cancer. 2006 Jul 31. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1252/ PMID: 20301430
  7. Vergés, B, et al. Pituitary disease in MEN type 1 (MEN1): data from the France-Belgium MEN1 multicenter study. J. Clin. Endocrinol. Metab. 2002; 87(2):457-65. doi: 10.1210/jcem.87.2.8145. PMID: 11836268
  8. Howe, JR, et al. The risk of gastrointestinal carcinoma in familial juvenile polyposis. Ann. Surg. Oncol. 1998; 5(8):751-6. doi: 10.1007/bf02303487. PMID: 9869523
  9. Bradley, KJ, et al. Uterine tumours are a phenotypic manifestation of the hyperparathyroidism-jaw tumour syndrome. J. Intern. Med. 2005; 257(1):18-26. doi: 10.1111/j.1365-2796.2004.01421.x. PMID: 15606373
  10. 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
  11. Half, E, et al. Familial adenomatous polyposis. Orphanet J Rare Dis. 2009; 4:22. doi: 10.1186/1750-1172-4-22. PMID: 19822006
  12. McWhinney, SR, et al. Familial gastrointestinal stromal tumors and germ-line mutations. N. Engl. J. Med. 2007; 357(10):1054-6. doi: 10.1056/NEJMc071191. PMID: 17804857
  13. Plail, RO, et al. Adenomatous polyposis: an association with carcinoma of the thyroid. Br J Surg. 1987; 74(5):377-80. PMID: 3036290
  14. Harach, HR, et al. Familial adenomatous polyposis associated thyroid carcinoma: a distinct type of follicular cell neoplasm. Histopathology. 1994; 25(6):549-61. PMID: 7698732
  15. Hulsebos, TJ, et al. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am. J. Hum. Genet. 2007; 80(4):805-10. doi: 10.1086/513207. PMID: 17357086
  16. 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
  17. Janoueix-Lerosey, I, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008; 455(7215):967-70. PMID: 18923523
  18. Eng, C. Cancer: A ringleader identified. Nature. 2008; 455(7215):883-4. PMID: 18923503
  19. Stratakis, CA, et al. Carney Complex. 2003 Feb 05. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301463
  20. Lohmann, DR, Gallie, BL. Retinoblastoma. 2000 Jul 18. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301625
  21. Dome, JS, Huff, V. Wilms Tumor Overview. 2003 Dec 19. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301471
  22. Goldman, M, et al. Renal abnormalities in beckwith-wiedemann syndrome are associated with 11p15.5 uniparental disomy. J. Am. Soc. Nephrol. 2002; 13(8):2077-84. PMID: 12138139
  23. Bertherat, J. Carney complex (CNC). Orphanet J Rare Dis. 2006; 1:21. PMID: 16756677
  24. 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
  25. 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
  26. Taylor, MD, et al. Mutations in SUFU predispose to medulloblastoma. Nat. Genet. 2002; 31(3):306-10. PMID: 12068298
  27. Benn, DE, et al. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes. J. Clin. Endocrinol. Metab. 2006; 91(3):827-36. PMID: 16317055
  28. Siitonen, HA, et al. Molecular defect of RAPADILINO syndrome expands the phenotype spectrum of RECQL diseases. Hum. Mol. Genet. 2003; 12(21):2837-44. PMID: 12952869
  29. Yamamoto, K, et al. A report of two cases of Werner's syndrome and review of the literature. J Orthop Surg (Hong Kong). 2003; 11(2):224-33. PMID: 14676353
  30. Ylisaukko-oja, SK, et al. Analysis of fumarate hydratase mutations in a population-based series of early onset uterine leiomyosarcoma patients. Int. J. Cancer. 2006; 119(2):283-7. PMID: 16477632
  31. Royer-Pokora, B, et al. Twenty-four new cases of WT1 germline mutations and review of the literature: genotype/phenotype correlations for Wilms tumor development. Am. J. Med. Genet. A. 2004; 127A(3):249-57. PMID: 15150775
  32. 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
  33. Zhang, J, et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N. Engl. J. Med. 2015; 373(24):2336-46. PMID: 26580448
  34. Plon, SE, Nathanson, K. Inherited susceptibility for pediatric cancer. Cancer J. 2005; 11(4):255-67. PMID: 16197716
  35. 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
  36. Naumova, A, Sapienza, C. The genetics of retinoblastoma, revisited. Am. J. Hum. Genet. 1994; 54(2):264-73. PMID: 8304343
  37. Witkowski, L, et al. The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type. Gynecol. Oncol. 2016; 141(3):454-60. PMID: 26975901
  38. Clarke, BA, et al. Loss of SMARCA4 (BRG1) Protein Expression by Immunohistochemistry in Small Cell Carcinoma of the Ovary, Hypercalcemic Type Distinguishes these Tumors from their Mimics. Histopathology. 2016. PMID: 27100627
  39. Citation unavailable PMID: 162461796
  40. Park, JR, et al. Neuroblastoma: biology, prognosis, and treatment. Pediatr. Clin. North Am. 2008; 55(1):97-120, x. PMID: 18242317
  41. Mossé, YP, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008; 455(7215):930-5. PMID: 18724359
  42. Chen, Y, et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature. 2008; 455(7215):971-4. PMID: 18923524
  43. Marvin, ML, et al. AXIN2-associated autosomal dominant ectodermal dysplasia and neoplastic syndrome. Am. J. Med. Genet. A. 2011; 155A(4):898-902. doi: 10.1002/ajmg.a.33927. PMID: 21416598
  44. Mazzoni, SM, et al. An AXIN2 Mutant Allele Associated With Predisposition to Colorectal Neoplasia Has Context-Dependent Effects on AXIN2 Protein Function. Neoplasia. 2015; 17(5):463-72. doi: 10.1016/j.neo.2015.04.006. PMID: 26025668
  45. Rai, K, et al. Comprehensive review of BAP1 tumor predisposition syndrome with report of two new cases. Clin. Genet. 2015. PMID: 26096145
  46. Popova, T, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am. J. Hum. Genet. 2013; 92(6):974-80. PMID: 23684012
  47. Prokofyeva, D, et al. Nonsense mutation p.Q548X in BLM, the gene mutated in Bloom's syndrome, is associated with breast cancer in Slavic populations. Breast Cancer Res. Treat. 2013; 137(2):533-9. PMID: 23225144
  48. Flanagan M, et al. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1398/ PMID: 20301572
  49. Bricaire, L, et al. Frequent large germline HRPT2 deletions in a French National cohort of patients with primary hyperparathyroidism. J. Clin. Endocrinol. Metab. 2013; 98(2):E403-8. PMID: 23293331
  50. Wang, O, et al. Novel HRPT2/CDC73 gene mutations and loss of expression of parafibromin in Chinese patients with clinically sporadic parathyroid carcinomas. PLoS ONE. 2012; 7(9):e45567. PMID: 23029104
  51. Carpten, JD, et al. HRPT2, encoding parafibromin, is mutated in hyperparathyroidism-jaw tumor syndrome. Nat. Genet. 2002; 32(4):676-80. PMID: 12434154
  52. Latchford, AR, et al. Juvenile polyposis syndrome: a study of genotype, phenotype, and long-term outcome. Dis. Colon Rectum. 2012; 55(10):1038-43. doi: 10.1097/DCR.0b013e31826278b3. PMID: 22965402
  53. 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
  54. Brioude, F, et al. Beckwith-Wiedemann syndrome: growth pattern and tumor risk according to molecular mechanism, and guidelines for tumor surveillance. Horm Res Paediatr. 2013; 80(6):457-65. PMID: 24335096
  55. Gizewska, M, et al. The significance of molecular studies in the long-term follow-up of children with beckwith- wiedemann syndrome. Turk. J. Pediatr. 2014; 56(2):177-82. PMID: 24911853
  56. Shuman, C, et al. Beckwith-Wiedemann Syndrome. 2000 Mar 03. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301568
  57. de, Kock, L, et al. Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathol. 2014; 128(1):111-22. doi: 10.1007/s00401-014-1285-z. PMID: 24839956
  58. Doros, L, et al. DICER1-Related Disorders. 2014 Apr 24. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK196157/ PMID: 24761742
  59. Rio, Frio, T, et al. DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA. 2011; 305(1):68-77. doi: 10.1001/jama.2010.1910. PMID: 21205968
  60. Bahubeshi, A, et al. Germline DICER1 mutations and familial cystic nephroma. J. Med. Genet. 2010; 47(12):863-6. doi: 10.1136/jmg.2010.081216. PMID: 21036787
  61. Wu, Y, et al. DICER1 mutations in a patient with an ovarian Sertoli-Leydig tumor, well-differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter. Eur J Med Genet. 2014; 57(11-12):621-5. doi: 10.1016/j.ejmg.2014.09.008. PMID: 25451712
  62. Slade, I, et al. DICER1 syndrome: clarifying the diagnosis, clinical features and management implications of a pleiotropic tumour predisposition syndrome. J. Med. Genet. 2011; 48(4):273-8. doi: 10.1136/jmg.2010.083790. PMID: 21266384
  63. Hill, DA, et al. DICER1 mutations in familial pleuropulmonary blastoma. Science. 2009; 325(5943):965. PMID: 19556464
  64. Alessandri, JL, et al. Perlman syndrome: report, prenatal findings and review. Am. J. Med. Genet. A. 2008; 146A(19):2532-7. PMID: 18780370
  65. Astuti, D, et al. Germline mutations in DIS3L2 cause the Perlman syndrome of overgrowth and Wilms tumor susceptibility. Nat. Genet. 2012; 44(3):277-84. PMID: 22306653
  66. Menko, FH, et al. Hereditary leiomyomatosis and renal cell cancer (HLRCC): renal cancer risk, surveillance and treatment. Fam. Cancer. 2014; 13(4):637-44. doi: 10.1007/s10689-014-9735-2. PMID: 25012257
  67. Schmidt, LS, Linehan, WM. Hereditary leiomyomatosis and renal cell carcinoma. Int J Nephrol Renovasc Dis. 2014; 7:253-60. PMID: 25018647
  68. Li, M, et al. GPC3 mutation analysis in a spectrum of patients with overgrowth expands the phenotype of Simpson-Golabi-Behmel syndrome. Am. J. Med. Genet. 2001; 102(2):161-8. PMID: 11477610
  69. Sajorda BJ, et al. Simpson-Golabi-Behmel Syndrome Type 1. 2006 Dec 19. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1219/ PMID: 20301398
  70. Cottereau, E, et al. Phenotypic spectrum of Simpson-Golabi-Behmel syndrome in a series of 42 cases with a mutation in GPC3 and review of the literature. Am J Med Genet C Semin Med Genet. 2013; 163C(2):92-105. PMID: 23606591
  71. Jennes, I, et al. Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb). Hum. Mutat. 2009; 30(12):1620-7. PMID: 19810120
  72. Kitsoulis, P, et al. Osteochondromas: review of the clinical, radiological and pathological features. In Vivo. 2008; 22(5):633-46. PMID: 18853760
  73. Jamsheer, A, et al. Mutational screening of EXT1 and EXT2 genes in Polish patients with hereditary multiple exostoses. J. Appl. Genet. 2014; 55(2):183-8. PMID: 24532482
  74. KROOTH, RS, et al. Diaphysial aclasis (multiple exostoses) on Guam. Am. J. Hum. Genet. 1961; 13:340-7. PMID: 13754517
  75. Hennekam, RC. Hereditary multiple exostoses. J. Med. Genet. 1991; 28(4):262-6. PMID: 1856833
  76. Schmale, GA, et al. The natural history of hereditary multiple exostoses. J Bone Joint Surg Am. 1994; 76(7):986-92. PMID: 8027127
  77. Smith, MJ, et al. Mutations in LZTR1 add to the complex heterogeneity of schwannomatosis. Neurology. 2015; 84(2):141-7. PMID: 25480913
  78. Piotrowski, A, et al. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas. Nat. Genet. 2014; 46(2):182-7. PMID: 24362817
  79. Paganini, I, et al. Expanding the mutational spectrum of LZTR1 in schwannomatosis. Eur. J. Hum. Genet. 2015; 23(7):963-8. PMID: 25335493
  80. Beckers, A, et al. Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. Endocr. Rev. 2013; 34(2):239-77. PMID: 23371967
  81. Igreja, S, et al. Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. Hum. Mutat. 2010; 31(8):950-60. PMID: 20506337
  82. Leontiou, CA, et al. The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. J. Clin. Endocrinol. Metab. 2008; 93(6):2390-401. PMID: 18381572
  83. Beckers, A, Daly, AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur. J. Endocrinol. 2007; 157(4):371-82. PMID: 17893250
  84. Daly, AF, et al. Aryl hydrocarbon receptor-interacting protein gene mutations in familial isolated pituitary adenomas: analysis in 73 families. J. Clin. Endocrinol. Metab. 2007; 92(5):1891-6. PMID: 17244780
  85. Vierimaa, O, et al. Pituitary adenoma predisposition caused by germline mutations in the AIP gene. Science. 2006; 312(5777):1228-30. PMID: 16728643
  86. Tichomirowa, MA, et al. High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. Eur. J. Endocrinol. 2011; 165(4):509-15. PMID: 21753072
  87. Raverot, G, et al. Familial pituitary adenomas with a heterogeneous functional pattern: clinical and genetic features. J. Endocrinol. Invest. 2007; 30(9):787-90. PMID: 17993773
  88. Rostomyan, L, et al. AIP mutations and gigantism. Ann. Endocrinol. (Paris). 2017; 78(2):123-130. PMID: 28483363
  89. Stiles, CE, Korbonits, M. Familial Isolated Pituitary Adenoma. 2016 Nov 11. In: Feingold, KR, et al, editors. Endotext (Internet). MDText.com, Inc.. PMID: 25905184
  90. Lloyd, C, Grossman, A. The AIP (aryl hydrocarbon receptor-interacting protein) gene and its relation to the pathogenesis of pituitary adenomas. Endocrine. 2014; 46(3):387-96. PMID: 24366639
  91. Gadelha, MR, et al. Genetics of pituitary adenomas. Front Horm Res. 2013; 41:111-40. PMID: 23652674
  92. Korbonits, M, Kumar, AV. AIP-Related Familial Isolated Pituitary Adenomas. 2012 Jun 21. In: Adam, MP, et al, editors. GeneReviews® (Internet). University of Washington, Seattle. PMID: 22720333
  93. Neklason, DW, et al. American founder mutation for attenuated familial adenomatous polyposis. Clin. Gastroenterol. Hepatol. 2008; 6(1):46-52. PMID: 18063416
  94. Mahamdallie, SS, et al. Mutations in the transcriptional repressor REST predispose to Wilms tumor. Nat. Genet. 2015; 47(12):1471-4. PMID: 26551668
  95. Chen, ZF, et al. NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis. Nat. Genet. 1998; 20(2):136-42. PMID: 9771705

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
AXIN2 NM_004655.3
BAP1 NM_004656.3
BLM NM_000057.3
BMPR1A* NM_004329.2
CDC73 NM_024529.4
CDKN1C NM_000076.2
DICER1 NM_177438.2
DIS3L2 NM_152383.4
EPCAM* NM_002354.2
EXT1 NM_000127.2
EXT2 NM_207122.1
FH NM_000143.3
GPC3 NM_004484.3
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
NBN NM_002485.4
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
RECQL4 NM_004260.3
REST NM_005612.4
RET NM_020975.4
SDHA* NM_004168.3
SDHAF2 NM_017841.2
SDHB NM_003000.2
SDHC NM_003001.3
SDHD NM_003002.3
SMAD4 NM_005359.5
SMARCA4 NM_001128849.1
SMARCB1 NM_003073.3
SMARCE1 NM_003079.4
STK11 NM_000455.4
SUFU NM_016169.3
TMEM127 NM_017849.3
TP53* NM_000546.5
TSC1 NM_000368.4
TSC2 NM_000548.3
VHL NM_000551.3
WRN* NM_000553.4
WT1 NM_024426.4

APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.
BMPR1A: Deletion/duplication analysis covers the promoter region.
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.
WRN: Deletion/duplication analysis is not offered for exons 10 or 11.