BrainTumorNext is a next generation sequencing panel that simultaneously analyzes 27 genes associated with increased risk for brain tumors and other cancers/tumors.


BrainTumorNext is a next generation sequencing panel that simultaneously analyzes 27 genes associated with increased risk for brain tumors and other cancers/tumors.

Ambry utilizes next generation sequencing (NGS) to offer a comprehensive panel for hereditary brain tumors. Genes on this panel include: AIP, ALK, APC, CDKN1B, CDKN2A, DICER1, MEN1, MLH1, MSH2, MSH6, NBN, NF1, NF2, PHOX2B, PMS2, POT1, PRKAR1A, PTCH1, PTEN, SMARCA4, SMARCB1, SMARCE1, SUFU, TP53, TSC1, TSC2, and VHL. Full gene sequencing and gross deletion/duplication analysis is performed for all 27 genes. Specific Site Analysis is available for individual gene mutations identified in a family.

Disease Name 
Brain tumors
Hereditary cancer
Li-Fraumeni syndrome
Lynch syndrome
Familial adenomatous polyposis
Gorlin syndrome
Tuberous sclerosis complex
von Hippel-Lindau disease
Carney complex
Disease Information 

Brain tumors are the 16th most common cancer diagnosed in men and women. Fewer than 1% of men and women in the U.S. will be diagnosed with a brain tumor/cancer at some point during their lives.1 The National Cancer Institute (NCI) estimates that approximately 23,700 new cases of brain and other nervous system tumors/cancer will be diagnosed in the U.S. in 2016.2 The median age at diagnosis is age 58, although 43.6% are diagnosed under age 54.2 The majority of brain tumors are sporadic, with some being hereditary and developing due to an inherited genetic mutation. Hereditary brain tumors may be diagnosed at younger ages (especially in childhood). 

BrainTumorNext Genes:

AIP mutations cause familial isolated pituitary adenomas (FIPA), an autosomal dominant condition. These occur in a familial setting in the absence of multiple endocrine neoplasia 1 (MEN1), Carney complex, or other known inherited conditions.  FIPA differs from MEN1 in terms of a lower proportion of prolactinomas and more frequent somatotropinomas in the FIPA cohort.3 Mutations in the AIP gene have been identified in 15-30% of cases of FIPA and have also been reported in individuals with sporadic pituitary adenomas.3,4 Compared to AIP mutation negative individuals with pituitary adenomas, individuals with mutations are more likely to have aggressive disease and present earlier in life.3 The median age of diagnosis of AIP-related FIPA is 23 years and penetrance estimates range from 33-66%.3,5

ALK heterozygous germline mutations in the ALK gene are associated with familial predisposition to neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma.6 Germline mutations in ALK have also been implicated in medulloblastoma risk, but further study is necessary.7  Penetrance for neuroblastoma is variable, and is estimated to be up to 57% across studies.8

APC germline mutations are the primary cause of familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP). FAP and AFAP are autosomal dominant colon cancer predisposition syndromes characterized by hundreds to thousands of adenomatous polyps in the internal lining of the colon and the rectum. They affect 1 in 8,000 to 1 in 10,000 individuals, and account for about 1% of all colorectal cancers.9  In individuals affected with classic FAP, colonic polyps generally begin developing at an average age of 16 years.10  In these families, colon cancer is inevitable without surgical intervention like colectomy, and the mean age of colon cancer diagnosis in untreated individuals is 35-40 years.11  Individuals with FAP or AFAP may also have increased risks to develop duodenal cancer, pancreatic cancer, papillary thyroid cancer, hepatoblastoma in childhood, and medulloblastoma.  Some individuals may also have non-malignant features such as osteomas, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and/or desmoid tumors.9

CDKN1B Heterozygous germline alterations are associated with multiple endocrine neoplasia type 4 (MEN4), characterized by parathyroid, anterior pituitary, and neuroendocrine tumors.12 Nearly 100% individuals with CDKN1B mutations develop hyperparathyroidism, however, penetrance estimates for other features of this syndrome are not currently available.13 MEN4 and multiple endocrine neoplasia type 1 share similar phenotypes, and mutations in CDKN1B account for approximately 1-3% of individuals with clinically diagnosed MEN1 lacking a germline mutation in the MEN1 gene.12,14

CDKN2A encodes two distinct proteins, p16 and p14ARF, which are both involved in cell cycle regulation. Germline p16/CDKN2A mutations are associated with familial atypical multiple mole melanoma (FAMMM) syndrome. FAMMM is an autosomal dominant disorder characterized by an increased risk for atypical mole malignant melanoma, often associated with dysplastic or atypical nevi.CDKN2A mutation carriers have an approximate 28-67% lifetime risk of developing melanoma, with penetrance estimates varying widely based on study design and geographic region.15-17 Individuals carrying CDKN2A mutations also have an approximate 17-25% lifetime risk for pancreatic cancer; however, recent reports suggest this risk may be as high as 58% and elevated further in smokers.18-20 Rare mutations that affect the p14ARF mutations have also been reported to predispose to melanoma and possibly pancreatic cancer.19,21,22

DICER1 mutations have been shown to cause a tumor predisposition syndrome associated with an increased risk for various benign and malignant tumors. Studies have demonstrated an increased risk for tumors including pleuropulmonary blastoma, cystic nephroma, ovarian sex cord stromal tumors (primarily Sertoli-Leydig cell tumors), multinodular goiter and thyroid cancer, embryonal rhabdomyosarcomas, ciliary body medulloepithelioma, nasal chondromesenchymal hamartomas, and pituitary blastoma, as well as various other tumor types. At this time, lifetime risks for each tumor type have not been well described.23-25

MEN1 mutations cause multiple endocrine neoplasia type 1 (MEN1) and familial isolated hyperparathyroidism (FIHP). FIHP is defined by primary hyperparathyroidism as the sole endocrinopathy in a family.26  In contrast, MEN1 is characterized by primary hyperparathyroidism due to parathyroid adenomas (present in over 90% of affected individuals), gastro-entero-pancreatic neuroendocrine tumors (in 30-70%), pituitary adenomas (in 30-60%), adrenocortical tumors (15-50%), bronchial and thymic carcinoids (up to 10%), facial angiofibromas, collagenomas, and lipomas.27-32 The majority of patients (94%) carrying a mutation in the MEN1 gene exhibit clinical or biochemical symptoms by age 50.33

MLH1, MSH2, MSH6, and PMS2 germline mutations are associated with Lynch syndrome (previously called hereditary non-polyposis colorectal cancer, HNPCC). Lynch syndrome is an autosomal dominant condition estimated to cause 2-5% of all colorectal cancer. It is associated with a significantly increased risk for colorectal cancer (up to 82% lifetime risk), uterine/endometrial cancer (25-60% lifetime risk in women), stomach cancer (6-13% lifetime risk), ovarian cancer (4-12% lifetime risk in women) and prostate cancer (up to 2 fold). Risk for cancer of the small bowel, hepatobiliary tract, upper urinary tract (including transitional cell carcinoma of the renal pelvis), brain, and sebaceous glands may also be elevated.34-38

NBN gene is involved in the Fanconi anemia (FA)-BRCA pathway, critical for DNA repair by homologous recombination, and interact in vivo with BRCA1 and/or BRCA2.39-41 Mutations in these genes are associated with an increased risk for female breast and ovarian cancer.41,43 NBN has more recently been associated an increased risk of prostate cancer and medulloblastoma.44-46 NBN is also associated with a rare autosomal recessive disorder that affects multiple body systems.   

NF1 mutations cause neurofibromatosis type 1 (NF1), an autosomal dominant disorder affecting multiple body systems. It is characterized by multiple café-au-lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and Lisch nodules. The most common neoplasms observed in individuals with NF1 include peripheral nerve sheath tumors, gastrointestinal stromal tumors (GIST), central nervous system gliomas, leukemias, paragangliomas (PGLs) and pheochromocytomas (PCCs), and breast cancer. Multiple population-based studies have demonstrated a 3 to 5-fold increase in lifetime breast cancer risk for women with NF1, with the highest risks for those less than 50 years of age.47 In addition, individuals with NF1 have an estimated lifetime risk for PGLs and PCCs of up to 7%.100

NF2 heterozygous germline pathogenic mutations cause neurofibromatosis type 2 (NF2), characterized by development of multiple nerve sheath tumors, most notably bilateral vestibular schwannomas (present in over 90% of individuals), as well schwannomas of other cranial nerves (in 24-51%), intracranial meningiomas (in 45-58%), and spinal tumors including meningiomas, schwannomas, gliomas, ependymomas, and rarely astrocytomas (combined 63-90%).48 Approximately 50% of all NF2 mutations are inherited while the remaining 50% are de novo events.  Of the NF2 mutations that are de novo events, up to 30% are mosaic.49

PHOX2B functions as a transcription factor involved in the development of several major noradrenergic neuron populations and the determination of neurotransmitter phenotype. Expansion of a 20 amino acid polyalanine tract in this protein by 5-13 aa has been associated with congenital central hypoventilation syndrome (CCHS), characterized by apparent hypoventilation due to autonomic nervous system dysregulation (ANSD) as well as abnormalities of neural crest-derived structures, such as Hirschsprung disease (HSCR), and tumors of neural crest origin.50 Heterozygous germline mutations outside the polyalanine repeat region predispose to neuroblastic tumors such as neuroblastoma, ganglioneuroblastoma, and ganglioneuroma, with or without other neurocristopathies of CCHS and HSCR.51 Genotype-phenotype correlations are under study to help better define disease mechanisms and the extent of overlap of the various phenotypes associated with PHOX2B mutations.52

POT1 heterozygous germline alterations have been identified in familial and unselected cases of glial tumors such as glioma, astrocytoma, and oligodendroglioma, and appear to demonstrate incomplete penetrance.53,54 Lifetime cancer risk estimates for POT1 mutation carriers are not currently available.

PRKAR1A heterozygous germline pathogenic mutations cause Carney Complex, which is characterized by primary pigmented nodular adrenocortical disease (PPNAD)(present in 26-60% of individuals), pituitary adenoma (in 10-12%), cardiac myxoma (in 32-53%), skin and breast myxomas (in 20-33%), thyroid nodules (in 25%) and/or carcinoma (in 2-5%), large-cell calicifying sertoli cell tumor (in 33-41%), and psammomatous melanotic schwannomas (in 8-10%). 55-58

PTCH1 mutations cause nevoid basal cell carcinoma syndrome (NBCCS), also referred to as Gorlin syndrome.  NBCCS/Gorlin syndrome is an autosomal dominant condition with a de novo mutation rate of approximately 20-30%, and up to 90% of affected individuals develop basal cell carcinoma. In addition, NBCCS can cause odontogenic keratocysts, congenital skeletal anomalies, cerebral calcifications, macrocephaly, polydactyly, intellectual disability, palmar epidermal pits, and cardiac and ovarian fibromas.59-63 Up to 5% of children with NBCCS develop medulloblastoma, also called primitive neuroectodermal tumor (PNET), most often the desmoplastic subtype. The diagnosis of NBCCS has historically been made based on clinical features.

PTEN is a gene associated with Cowden syndrome (CS), PTEN hamartoma tumor syndrome (PHTS), Bannayan-Riley-Ruvalcaba syndrome, Proteus syndrome, and autism spectrum disorder. CS is a multiple hamartoma syndrome with a high risk of developing tumors of the thyroid, breast, and endometrium. Mucocutaneous lesions, thyroid abnormalities, fibrocystic disease, multiple uterine leiomyomata, and macrocephaly can also be seen. Affected individuals have a lifetime risk of up to 50% for breast cancer, 10% for thyroid cancer, and 5-10% for endometrial cancer. Over 90% of individuals with CS will express some clinical manifestations by their twenties.64,65  Recent studies noted increased risks for renal cell cancer, colorectal cancer, and other cancers.66,67  One study quotes up to a 31-fold increase in RCC risk for PTEN mutation carriers as compared to the general population.68

SMARCA4 truncating mutations cause rhabdoid tumor predisposition syndrome type 2. SMARCA4-associated tumors are highly aggressive and include atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system, malignant rhabdoid tumors of the kidney, and small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).  The lifetime cancer risks for SMARCA4 mutation carriers has yet to be defined; however, age of onset and penetrance are extremely variable, with some carriers presenting prenatally while others remain unaffected through adulthood.69-72

SMARCB1 heterozygous germline pathogenic mutations cause rhabdoid tumor predisposition syndrome type 1 (RTPS1) and schwannomatosis. Individuals with RTPS1 are at risk to develop atypical teratoid/rhabdoid tumors of the CNS and malignant rhabdoid tumors of the kidney.73 Age of onset and penetrance are extremely variable, with some carriers presenting at birth while others remain unaffected through adulthood.74 Approximately 5% of individuals with schwannomatosis due to SMARCB1 mutation also develop meningiomas.73 SMARCB1 mutations are thought to account for 35% of AT/RT, 48% of familial schwannomatosis, and 10% of sporadic schwannomatosis.73,74 It is believed that individuals with non-truncating mutations in SMARCB1 have a low risk for AT/RT, but genotype-phenotype correlations are still under study to help better define disease mechanisms and the extent of phenotypic overlap of the three syndromes associated with SMARCB1 mutations.73

SMARCE1 heterozygous loss of function alterations such as truncations, frameshifts, and gross deletions cause predisposition for multiple spinal and cranial clear cell meningiomas.75,76 The lifetime risk for clear cell meningiomas in SMARCE1 mutation carriers has yet to be defined; however, age of onset and penetrance are extremely variable, with some carriers presenting in early childhood while others remain unaffected through adulthood. 76

SUFU heterozygous germline pathogenic mutations cause nevoid basal cell carcinoma syndrome (NBCCS), also referred to as Gorlin syndrome. NBCCS/Gorlin syndrome is a genetically and clinically heterogeneous condition characterized by multiple basal cell carcinomas, jaw keratocysts, skeletal anomalies, palmar and plantar pits, calicification of the falx cerebri, coarse facial features, macrocephaly, increased risk for childhood-onset desmoplastic medulloblastoma, ovarian and cardiac fibromas, ocular anomalies, and cleft lip and palate.77 Approximately 5% of individuals with NBCCS will develop medulloblastoma, however current data suggests the risk is higher (~30%) in individuals with mutations in SUFU than in other genes that cause NBCCS.78,79 Some individuals with mutations in SUFU develop isolated medulloblastoma without other symptoms of NBCCS.79 SUFU has also been implicated in familial meningioma.80

TP53 is a tumor suppressor gene, and germline mutations within it are associated with Li-Fraumeni syndrome (LFS). An individual carrying a TP53 mutation has a 21-49% lifetime risk of developing cancer by age 30 and a lifetime cancer risk of 68-93%.81  The most common tumor types observed in LFS families include soft tissue and osteosarcomas, breast cancer, brain tumors (including astrocytomas, glioblastomas, medulloblastomas and choroid plexus carcinomas), and adrenocortical carcinoma (ACC); other cancers, including colorectal, gastric, ovarian, pancreatic, and renal, have also been reported.82,83  Studies have shown that a small percentage of women with early onset breast cancer that do not carry BRCA1 and BRCA2 mutations are identified to have mutations in TP53.84-86

TSC1 and TSC2 are genes associated with tuberous sclerosis complex (TSC), a multi-system neurocutaneous disorder characterized by presence of benign hamartomas in multiple tissues and organs, seizures, and intellectual disability.87 Benign hamartomas can be found in the heart (rhabdomyomas), brain (astrocytomas), kidneys (angiomyolipomas), skin, eyes, lungs (pulmonary lymphangioleimyomatosis), skeleton, and endocrine glands.87-91 The lifetime risk of renal cancer development in TSC is 2-5%.88

VHL mutations are associated with von Hippel-Lindau disease (VHL). VHL is an autosomal dominant cancer predisposition syndrome with about a 20% de novo mutation(139) rate and an estimated incidence of 1 in 36,000.92  VHL is characterized by renal tumors, adrenal pheochromocytoma (PCC), retinal angiomas, central nervous system hemangioblastomas, pancreatic cysts, and neuroendocrine tumors. The associated lifetime risk of RCC in those with VHL is estimated at 25-70%, depending on disease subtype. VHL-associated renal tumors tend to be earlier-onset (average age of diagnoses is 39 years) and multifocal.93 Published literature supports that patients carrying a partial germline VHL gene deletion have a higher RCC risk than those carrying full-gene deletions.94,95


Testing Benefits & Indication 

Indications for Testing

BrainTumorNext may be appropriate in the following situations, combined with common red flags for hereditary cancer:

  • Early-onset brain tumor(s) (diagnosed <50 years of age)
  • Multiple primary cancers in one person (e.g. brain tumor and colorectal cancer)
  • Multiple close relatives* with brain tumors
  •  A family history of a mutation in a gene that predisposes to brain tumors

* On the same side of the family

Common Red Flags for Hereditary Cancer

  • Cancer diagnosed at a younger age than expected for the general population (≤ 50 years, for most cancers)
  • Cancer diagnosed across generations, and in multiple generations within a family, especially when diagnosed younger than average
  • Individual with multiple primary cancers (either in paired organs or in different organs)
  • A pattern of cancer in the family that is typical of a known cancer predisposition syndrome (e.g. colon and uterine cancer in Lynch syndrome, or breast and pancreatic cancer with PALB2 mutations) 

The American Society of Clinical Oncology (ASCO) recommends that genetic testing be offered to individuals with suspected inherited (genetic) cancer risk in situations where test results can be interpreted, and when they affect medical management of the patient. It is sufficient for cancer risk assessment to evaluate genes of established clinical utility that are suggested by the patient’s personal and/or family history.96-99

Benefits of Testing

Identifying patients with an inherited susceptibility for certain cancers can help with medical management and risk assessment. For example, this information can:

  • Modify cancer surveillance options and age of initial screening
  • Suggest specific early screening measures (e.g. begin colonoscopy earlier with MMR mutations and TP53 mutations, whole body rapid MRI and other TP53 mutation-based screenings)
  • Clarify and stratify personal and familial cancer risks, based on gene-specific cancer associations (e.g. risk for colon, uterine, stomach, and small bowel cancer with MLH1 mutations)
  • Offer treatment guidance (e.g. avoidance of radiation-based treatment methods for individuals with aTP53 mutation)
  • Identify other at-risk family members
  • Provide guidance with new gene-specific treatment options and risk reduction measures as they emerge
Test Description 

BrainTumorNext analyzes 27 genes (listed above). All genes are evaluated by next generation sequencing (NGS) or Sanger sequencing of all coding domains, and well into the flanking 5’ and 3’ ends of all the introns and untranslated regions. In addition, sequencing of the promoter region is performed for the following genes: PTEN (c.-1300 to c.-745), MLH1 (c.-337 to c.-194), and MSH2 (c.-318 to c.-65). The inversion of coding exons 1-7 of the MSH2 gene is detected by NGS and confirmed by PCR and agarose gel electrophoresis. For ALK, only variants located within the kinase domain (c.3286-c.4149) are reported. For PHOX2B, the polyalanine repeat region is excluded from analysis. Clinically significant intronic findings beyond 5 base pairs are always reported. Intronic variants of unknown or unlikely clinical significance are not reported beyond 5 base pairs from the splice junction. Additional Sanger sequencing is performed for any regions missing or with insufficient read depth coverage for reliable heterozygous variant detection. Reportable small insertions and deletions, potentially homozygous variants, variants in regions complicated by pseudogene interference, and single nucleotide variant calls not satisfying 100x depth of coverage and 40% het ratio thresholds are verified by Sanger sequencing.101 Gross deletion/duplication analysis is performed for the covered exons and untranslated regions of all 27 genes using read-depth from NGS data with confirmatory multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray. For APC, all promoter 1B gross deletions as well as single nucleotide substitutions within the promoter 1B YY1 binding motif are analyzed and reported. If a deletion is detected in exons 13, 14, or 15 of PMS2, double stranded sequencing of the appropriate exon(s) of the pseudogene, PMS2CL, will be performed to determine if the deletion is located in the PMS2 gene or pseudogene.

Mutation Detection Rate 

BrainTumorNext can detect >99.9% of described mutations in the included genes listed above, when present (analytic sensitivity).

Specimen Requirements 

Complete specimen requirements are available here or by downloading the PDF found above on this page.

Turnaround Time 
8847 BrainTumorNext 14 - 21


  1. Surveillance, Epidemiology, and End Results Program. Cancer Stat Fact Sheets  [Accessed October 20, 2016]. Available from:
  2. National Cancer Institute.  [Accessed October 20, 2016, 2016]. Available from:
  3. Daly AF et al. Clinical characteristics and therapeutic responses in patients with germ-line AIP mutations and pituitary adenomas: an international collaborative study. J. Clin. Endocrinol. Metab., 2010 Nov;95:E373-83.
  4. Beckers A, Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol. 2007 Oct;157(4):371-82.
  5. Naves LA et al. Variable pathological and clinical features of a large Brazilian family harboring a mutation in the aryl hydrocarbon receptor-interacting protein gene. Eur. J. Endocrinol., 2007 Oct;157:383-91.
  6. Bourdeaut T, et al. ALK germline mutations in patients with neuroblastoma: a rare and weekly penetrant syndrome. Eur J Hum Genet. 2012 Mar;20(3):291-7.
  7. Coco  S, et al. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma. J Hum Genet. 2012 Oct;57(10)682-4.
  8. Eng C. Cancer: A ringleader identified. Nature. 2008 Oct 16:455(7215):883-4.
  9. Lipton L and Tomlinson I. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006. 5(3):221-6.
  10. Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991. 100(6):1658-64.
  11. Pedace L, et al. Identification of a novel duplication in the APC gene using multiple ligation probe amplification in a patient with familial adenomatous polyposis. Cancer Genet Cytogenet. 2008. 182(2):130-5.
  12. Agarwal SK, et al. Rare germline mutations in cyclin-dependent kinase inhibitor genes in multiple endocrine neoplasia type 1 and related states. J Clin Endocrinol Metab. 2009 May;94(5):1826-34.
  13. Georgitsi M. MEN-4 and other multiple endocrine neoplasia due to cyclin-dependent kinase inhibitors (p27(Kip1) and p18(INK4C)) mutations. Best Pract Res Clin Endocrinol Metab. 2010 Jun;24(3):425-37.
  14. Occhi G, et al. A novel mutation in the upstream open reading frame of the CDKN1B gene causes a MEN4 phenotype. PLoS Genet. 2013 Mar;9(3):e1003350.
  15. Begg CB, et al. Lifetime risk of melanoma in CDKN2A mutation carriers in a population-based sample. J Natl Cancer Inst. 2005. 97(20):1507-15.
  16. Bishop DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002. 94(12):894-903.
  17. Cust AE, et al. Melanoma risk for CDKN2A mutation carriers who are relatives of population-based case carriers in Australia and the UK. J Med Genet. 2011. 48(4):266-72.
  18. Vasen HF, et al. Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden). Int J Cancer. 2000. 87(6):809-11.
  19. McWilliams RR, et al. Prevalence of CDKN2A mutations in pancreatic cancer patients: implications for genetic counseling. Eur J Hum Genet. 2011. 19(4):472-8.
  20. de Snoo FA, et al. Increased risk of cancer other than melanoma in CDKN2A founder mutation (p16-Leiden)-positive melanoma families. Clin Cancer Res. 2008. 14(21):7151-7.
  21. Laud K, et al. Comprehensive analysis of CDKN2A (p16INK4A/p14ARF) and CDKN2B genes in 53 melanoma index cases considered to be at heightened risk of melanoma. J Med Genet. 2006. 43(1):39-47.
  22. Binni F, et al. Novel and recurrent p14 mutations in Italian familial melanoma. Clin Genet. 2010. 77(6):581-6.
  23. 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.
  24. Schultz KA, et al. DICER1-pleuropulmonary blastoma familial tumor predisposition syndrome: a unique constellation of neoplastic conditions. Pathol Case Rev. 2014. 19(2):90-100.
  25. de Kock L, et al. Pituitary blastoma: a pathognomonic feature of germline DICER1 mutations. Acta Neuropathol. 2014. 128(1):111-22.
  26. Hannan FM, et al. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1gene. Nature Clinical Practice Endocrinology & Metabolism. 2008;4(1):53-8.
  27. Machens A, et al. Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers. Clinical Endocrinology. 2007;67:613-22.
  28. Thakker RV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(2990-3011):2990.
  29. Carty SE, et al. The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery. 1998;124(6):1106-14.
  30. Gibril F, et al. Prospective study of thymic carcinoids in patients with multiple endocrine neoplasia type 1. J Clin Endocrinol Metab. 2003;88(3):1066-81.
  31. Marx SJ, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med. 1998;129:484-94.
  32. Waldmann J, et al. Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbecks Arch Surg. 2007;392:437-43.
  33. Chandrasekharappa SC, et al. Positional cloning of the gene for multiple endocrine neoplasia–type 1. Science. 1997;276:404-7.
  34. Hegde MR and Roa BB. Genetic testing for hereditary nonpolyposis colorectal cancer (HNPCC) current protocols in human genetics. 2009. 61(Unit 10.12):10.12.1-10.12.28.
  35. Capelle LG, et al. Risk and epidemiological time trends of gastric cancer in Lynch syndrome carriers in the Netherlands. Gastroenterology. 2010. 138(2):487-92.
  36. Bonadona V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6genes in Lynch syndrome. JAMA. 2011. 305(22):2304-10.
  37. Engel C, et al. Risks of less common cancers in proven mutation carriers with Lynch syndrome. J Clin Oncol. 2012. 30(35):4409-15.
  38. Win AK, et al. Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study. J Clin Oncol. 2012. 30(9):958-64.
  39. Walsh T, et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci U S A. 2010;107(28):12629-33. 
  40. Pennington KP and Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecologic oncology. 2012;124(2):347-53. 
  41. Damiola F, et al. Rare key functional domain missense substitutions in MRE11A, RAD50, and NBN contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2014;16(3):R58.
  42. Bogdanova N et al. Nijmegen Breakage Syndrome mutations and risk of breast cancer. Int J Cancer.2008 Feb 15;122(4):802-6.
  43. Ramus et al. Germline mutations in the BRIP1, BARD1, PALB2, and NBN genes in women with ovarian cancer. J Natl Cancer Inst. 2015. 107(11). 
  44. Cybulski C et al. An inherited NBN mutation is associated with poor prognosis prostate cancer. Br J Cancer. 2013;108:461–468
  45. Pritchard CC et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016 Aug 4;375(5):443-53.
  46. Ciara E et al. Heterozygous germ-line mutations in the NBN gene predispose to medulloblastoma in pediatric patients. Acta Neuropathol. 2010 Mar;119(3):325-34.
  47. Madanikia S et al. Increased risk of breast cancer in women with NF1. Am J Med Genet A. 2012 Dec;158A(12):3056-60
  48. Asthagiri AR, et al. Neurofibromatosis type 2. Lancet. 2009 Jun 6;373(9679:1974-86.
  49. Petrilli, AM et al. Role of Merlin/NF2 inactivation in tumor biology.Oncogene. 2016, 35(5): 537-548
  50. Weese-Mayer DE, et al. An official ATS clinical policy statement: Congenital central hypoventilation syndrome: genetic basis, diagnosis, and management.Am J Respir Crit Care Med. 2010 Mar 15;181(6):626-44
  51. Heide S, et al. Oncologic phenotype of peripheral neuroblastic tumors associated with PHOX2B non-polyalanine repeat expansion mutations. Pediatr Blood Cancer. 2016 Jan;63(1):71-7.
  52. Trochet D, et al. Molecular consequences of PHOX2B missense, frameshift and alanine expansion mutations leading to autonomic dysfunction. Hum Mol Genet. 2005 Dec 1;14(23):3697-708.
  53. Bainbridge MN, et al. Germline mutations in shelterin complex genes are associated with familial glioma. J Natl Cancer Inst. 2014 Dec 7;107(1):384.
  54. Jones S, et al. Personalized genomic analyses for cancer mutation discovery and interpretation. Sci Transl Med. 2015 Apr 15;7(283):283ra53.
  55. Bertherat J, et al. Mutations in regulatory subunit type 1A of cyclic adenosine 5'-monophosphate-dependent protein kinase (PRKAR1A): phenotype analysis in 353 patients and 80 different genotypes. J Clin Endocrinol Metab. 2009 Jun;94(6):2085-91
  56. Groussin L et al. Molecular analysis of the cyclic AMP-dependent protein kinase A (PKA) regulatory subunit 1A (PRKAR1A) gene in patients with Carney complex and primary pigmented nodular adrenocortical disease (PPNAD) reveals novel mutations and clues for pathophysiology: augmented PKA signaling is associated with adrenal tumorigenesis in PPNAD. Am J Hum Genet. 2002 Dec;71(6):1433-42.
  57. Mateus C, et al. Heterogeneity of skin manifestations in patients with Carney complex. J Am Acad Dermatol. 2008 Nov;59(5):801-10.
  58. Stratakis CA, et al. Clinical and molecular features of the Carney complex: diagnostic criteria and recommendations for patient evaluation. J Clin Endocrinol Metab. 2001 Sep;86(9):4041-6.
  59. Evans DG, et al. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A:327–332.
  60. Soufir N, et alPTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study. Br J Cancer. 2006;95(4):548-553.
  61. Joshi PS, et al. Gorlin-Goltz syndrome. Dent Res J (Isfahan). 2012;9(1):100-106.
  62. Li TJ, et alPTCH germline mutations in Chinese nevoid basal cell carcinoma syndrome patients. Oral Dis. 2008;14(2):174-179.
  63. Yamamoto K, et al. Further delineation of 9q22 deletion syndrome associated with basal cell nevus (Gorlin) syndrome: report of two cases and review of the literature. Congenit Anom (Kyoto).2009;49(1):8-14.
  64. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000. 37(11):828-30.
  65. Starink TM, et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet. 1986. 29(3):222-33.
  66. Heald B, et al. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010. 139(6):1927-33.
  67. Tan MH, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012. 18(2):400-7.
  68. Mester JL, et al. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology. 2012. 79(5):1187 e1-7.
  69. Hasselblatt M, et al. Nonsense mutation and inactivation of SMARCA4 (BRG1) in an atypical teratoid/rhabdoid tumor showing retained SMARCB1 (INI1) expression. The American Journal of Surgical Pathology. 2011;35:933-5
  70. Schneppenheim R, et al. Germline nonsense mutation and somatic Inactivation of SMARCA4/BRG1in a family with rhabdoid tumor predisposition syndrome. Am J Hum Genet. 2010;86:279-84.
  71. Witkowski L, et al. Germline and somatic SMARCA4 mutations characterize small cell carcinoma of the ovary, hypercalcemic type. Nat Genet. 2014;46(5):438-45.
  72. Witkowski L, et al. Familial rhabdoid tumour ’avant la lettre’—from pathology review to exome sequencing and back again. Journal of Pathology. 2013;231:35-43.
  73. Smith, MJ et al. SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors. Cancer Genet. 2014, 207(9): 373-378.
  74. Eaton KW et al. Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer 2011 Jan;56(1):7-15.
  75. Smith, MJ et al. Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat Genet. 2013, 45(3): 295-298.
  76. Smith, MJ et al. Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. J Pathol. 2014, 234(4): 436-440.
  77. Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med. 6(6):530-9.
  78. Smith MJ, et al. Germline mutations in SUFU cause Gorlin syndrome-associated childhood medulloblastoma and redefine the risk associated with PTCH1 mutations. J Clin Oncol. 2014 Dec 20;32(36):4155-61.
  79. Brugières L, et al. Incomplete penetrance of the predisposition to medulloblastoma associated with germ-line SUFU mutations. J Med Genet. 2010 Feb;47(2):142-4.
  80. Aavikko M, et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet. 2012 Sep 7;91(3):52-6.
  81. Hwang SJ, et al. Germline p53 mutations in a cohort with childhood sarcoma: sex differences in cancer risk. Am J Hum Genet. 2003. 72(4):975-83.
  82. Olivier M, et al. Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003. 63(20):6643-50.
  83. Birch JM, et al. Prevalence and diversity of constitutional mutations in the p53 gene among 21 Li-Fraumeni families. Cancer Res. 1994. 54(5):1298-304.
  84. Walsh T, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer. JAMA. 2006. 295(12):1379-88.
  85. Gonzalez KD, et al. Beyond Li-Fraumeni syndrome: clinical characteristics of families with p53germline mutations. J Clin Oncol. 2009. 27(8):1250-6.
  86. McCuaig JM, et al. Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer. 2012. 11(4):607-13.
  87. Sancak O, et al. Mutational analysis of the TSC1 and TSC2 genes in a diagnostic setting: genotype--phenotype correlations and comparison of diagnostic DNA techniques in tuberous sclerosis complex. Eur J Hum Genet. 2005. 13(6):731-41.
  88. Borkowska J, et al. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011. 50(1):13-20.
  89. Hoogeveen-Westerveld M, et al. Functional assessment of TSC1 missense variants identified in individuals with tuberous sclerosis complex. Hum Mutat. 2012. 33(3):476-9.
  90. Rodrigues DA, Gomes CM, Costa IM. Tuberous sclerosis complex. An Bras Dermatol. 2012. 87(2):184-96.
  91. Sasongko TH, et al. Novel mutations in 21 patients with tuberous sclerosis complex and variation of tandem splice-acceptor sites in TSC1 exon 14. Kobe J Med Sci. 2008. 54(1):E73-81.
  92. Barrisford GW, et al. Familial renal cancer: molecular genetics and surgical management. Int J Surg Oncol. 2011. 2011:658767.
  93. Lonser RR, et al. von Hippel-Lindau disease. Lancet. 2003. 361(9374):2059-67.
  94. Rini BI, Campbell SC, Rathmell WK. Renal cell carcinoma. Curr Opin Oncol. 2006. 18(3):289-96.
  95. Barrisford GW, et al. Familial renal cancer: molecular genetics and surgical management. Int J Surg Oncol. 2011. 2011:658767.
  96. Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol. 1996 May;14(5):1730-6.
  97. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. J Clin Oncol. 2003 Jun 15;21(12):2397-406.
  98. Robson ME et al. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010 Feb 10;28(5):893-901.
  99. Robson ME et al. American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility. J Clin Oncol. 2015 Nov 1;33(31):3660-7.
  100. Fishbein L and Nathanson K. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 2012 Jan-Feb;205(1-2):1-11.
  101. Mu W, et al. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J Mol Diagn. 2016. 18(6):923-932