CancerNext-ExpandedTM is a next generation sequencing panel that simultaneously analyzes 67 genes associated with increased risks for brain, breast, colon, ovarian, pancreatic, prostate, renal, uterine, and many other cancers.



CancerNext-ExpandedTM is a next generation sequencing panel that simultaneously analyzes 67 genes associated with increased risks for brain, breast, colon, ovarian, pancreatic, prostate, renal, uterine, and many other cancers.


Ambry utilizes next generation sequencing (NGS) to offer CancerNext-Expanded, its comprehensive hereditary pan-cancer panel.  Genes on this panel include: AIP, ALK, APC, ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, BMPR1A, CDH1, CDK4, CDKN1B, CDKN2A, CHEK2, DICER1, EPCAM, FANCC, FH, FLCN, GALNT12, GREM1, HOXB13, MAX, MEN1, MET, MITF, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, NF1, NF2, PALB2, PHOX2B, PMS2, POLD1, POLE, POT1, PRKAR1A, PTCH1, PTEN, RAD50, RAD51C, RAD51D, RB1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHD, SMAD4, SMARCA4, SMARCB1, SMARCE1, STK11, SUFU, TMEM127, TP53, TSC1, TSC2, VHL, XRCC2. Full gene sequencing is performed for 65 of the genes (excluding EPCAM and GREM1). For MITF, only the status of the c.952G>A (p.E318K) alteration is analyzed and reported. Gross deletion/duplication analysis is performed for 66 genes (excluding MITF). Specific Site Analysis is available for individual gene mutations identified in a family.

Disease Name 
Brain tumors
Breast cancer
Colorectal cancer
Hereditary cancer
Kidney cancer
Ovarian cancer
Pancreatic cancer
Prostate cancer
Uterine cancer
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).  

Breast cancer is the most common cancer in women in developed countries, affecting about 1 in 8 (12.5%) women in their lifetime.1 The National Cancer Institute (NCI) estimates that approximately 231,840 new cases of female breast cancer and 2,350 new cases of male breast cancer will be diagnosed in the U.S. in 2015.2 The majority of breast cancers are sporadic, but 5-10% are due to inherited causes.  Hereditary breast cancer tends to occur earlier in life than non-inherited sporadic cases, and is more likely to occur in both breasts. The highly penetrant genes, BRCA1 and BRCA2, appear to be responsible for around half of hereditary breast cancer.3-5  However, additional genes have been discovered that are associated with increased breast cancer risk as well.3-7  Mutations in the genes included in CancerNext-Expanded can confer an estimated 20–87% lifetime risk for breast cancer.  Some of these genes have also been associated with increased risks for other cancers, such as pancreatic cancer with PALB2, ovarian cancer with BRCA1, BRCA2, RAD51C (and others), and sarcoma with TP53.8-12

Colorectal cancer (CRC) affects about 1 in 20 (5%) men and women in their lifetime.1   The NCI estimates that approximately 132,700 new cases will be diagnosed and 49,700 CRC deaths will occur in the U.S. in 2015.2  The majority of CRC is sporadic, but approximately 30% are familial, a subset of which have a strong genetic cause.  Lynch syndrome is the most common form of hereditary CRC, but several other genes are associated with increased CRC risk as well.13

Kidney cancer affects about 1 in 60 (1.6%) of men and women in the U.S. in their lifetime and it is the seventh and eighth most common cancer in men and women, respectively.1 Renal cell carcinoma (RCC) is a complex disease with a diverse spectrum of tumor subtypes, including clear cell or conventional (70-80%), papillary type 1 and type 2 (10-15%), chromophobe (3-5%), and collecting duct (1%).14 3-5% of RCC cases are hereditary15-17 and occur as a result of an inherited mutation in one or more genes. Unlike sporadic RCC cases, hereditary RCC is often characterized by earlier disease onset and/or multifocal or bilateral tumors.14

Ovarian cancer is the fifth most common cancer among women in developed countries, affecting approximately 1 in 71 (1.4%) women in their lifetime.1   The NCI estimates that approximately 21,290 new cases of ovarian cancer will be diagnosed and 14,180 ovarian cancer deaths will occur in the U.S. in 2015.2  It is the leading cause of death from gynecologic malignancy, usually characterized by advanced presentation with regional dissemination in the peritoneal cavity. Epithelial ovarian cancer is the most common form, and up to 25% of epithelial cases may be due to inherited gene mutations.18,19 BRCA1 and BRCA2 are the most common causes of hereditary ovarian cancer, but several other genes are associated with increased ovarian cancer risk as well.11,18,20,21

Pancreatic cancer affects about 1 in 65 (1.5%) of men and women in their lifetime.1  The National Cancer Institute (NCI) estimates that approximately 48,960 new cases of pancreatic cancer will be diagnosed in the U.S. in 2015.2  Approximately 95% of pancreatic cancers are pancreatic adenocarcinomas of the exocrine gland (which produces enzymes for food digestion). Neuroendocrine/islet cell tumors of the endocrine gland (a gland that produces insulin and regulates blood sugar) make up the other 5% of pancreatic cancer subtypes.  While the majority of pancreatic cancers are sporadic, approximately 5-10% of pancreatic cancer cases are familial, often occurring in families with multiple affected individuals.23 Multiple genes are associated with increased pancreatic cancer susceptibility.   

Paragangliomas (PGLs) are often benign, neuroendocrine tumors of the autonomic nervous system originating from the external ganglia. Pheochromocytomas (PCCs) are PGLs that are confined to the adrenal medulla. PGLs are further subdivided into sympathetic and parasympathetic tumors, depending upon their site of origin. Sympathetic PGLs commonly hypersecrete catecholamines and are typically located in the chest, abdomen and pelvis. Parasympathetic PGLs are primarily non-secretory and occur along the nerves in the head, the neck, and the upper mediastinum (termed head and neck PGLs or HNPGLs).24,25 The prevalence of PGLs in the U.S. is 1 in 2,500 to 1 in 6,500, although this is likely an underestimate. The average age of diagnosis is between 40-50 years.25,26 Approximately 75% of PGL/PCCs are benign; however, morbidity and mortality are associated with high levels of circulating catecholamines, which can lead to hypertension and stroke.24,26 Published population studies have found that at least 10-30% individuals with PGL/PCCs have an inherited germline mutation in one of the known susceptibility genes.24,27-29

Prostate cancer is the second most common cancer in men in the United States, after skin cancer.1 The National Cancer Institute (NCI) estimates that approximately 180,890 new cases of prostate cancer will be diagnosed in the U.S. in 2016.2 The majority of prostate cancer is sporadic and diagnosed over the age of 65. Some prostate cancer may be hereditary and develop due to an inherited genetic mutation. Hereditary prostate cancer may be diagnosed at younger ages and may also be more aggressive. For example, BRCA1 and BRCA2 gene mutations have been shown to be associated with more aggressive prostate cancer, including a higher likelihood of nodal involvement and distant metastasis.30

Uterine cancer affects about 1 in 38 (2.6%)  women in their lifetime.1 The NCI estimates that approximately 54,870 new cases of uterine cancer will be diagnosed and 10,170 uterine cancer deaths will occur in the U.S. in 2015.2 Increased risk for uterine cancer has been identified in a number of hereditary cancer syndromes, including Lynch syndrome and Cowden syndrome.

CancerNext-Expanded Genes

CancerNext-Expanded is an NGS cancer panel that simultaneously analyzes 67 genes associated with an increased risk for several cancers. While mutations in each gene on this panel may be individually rare, they collectively account for a significant amount of hereditary cancer susceptibility. This panel may be appropriate in a number of scenarios, particularly if the family history shares features of several different hereditary cancer syndromes with multiple cancer types.

CancerNext Genes

The following genes are included in CancerNext and CancerNext-Expanded:

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.31 In individuals affected with classic FAP, colonic polyps generally begin developing at an average age of 16 years.32 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.33 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.31

ATM is a gene associated with an autosomal recessive condition called ataxia-telangiectasia (AT). AT is characterized by progressive cerebellar ataxia with onset between ages 1 and 4, telangiectasia of the conjunctivae, oculomotor apraxia, immune defects, and a predisposition to malignancy, particularly leukemia and lymphoma. Women who carry ATM mutations also have an estimated 2-4 fold increased risk for breast cancer.34 Cancer risk estimates for male ATM mutation carriers are not currently available. Recent studies have also reported ATM germline mutations in individuals with familial pancreatic cancer. In one of these studies, ATM mutations were identified in 4/87 (4.6%) families with more than three affected members.35

BRCA1 and BRCA2 are tumor suppressor genes inherited in an autosomal dominant pattern. Mutations in these two highly penetrant genes increase the chance for cancer of the breast, ovaries (including primary peritoneal and fallopian tube), pancreas, and prostate. Studies suggest female BRCA1 mutation carriers have a 57-87% lifetime risk to develop breast cancer and a 39-40% lifetime risk to develop ovarian cancer by age 70.8-10,36-38 Male BRCA1 mutation carriers have a cumulative breast cancer lifetime risk of about 1.2% by age 70.39,40 Similar studies suggest female BRCA2 mutation carriers have a 45-84% lifetime risk to develop breast cancer and an 11-18% risk to develop ovarian cancer by age 70.8-10,41,42  Male BRCA2 mutation carriers have up a 15% lifetime prostate cancer risk and a cumulative lifetime breast cancer risk of 6.8% by ages 65 and 70 respectively.39,40,42,43 BRCA1/2 mutation carriers may also be at an increased risk for melanoma, pancreatic cancer, and potentially other cancers.44 BRCA2 is also known as FANCD1. Individuals who inherit a BRCA2/FANCD1 mutation from each parent may have a rare autosomal recessive condition called Fanconi anemia type D1 (FA-D1), which affects multiple body systems. 

BARD1, BRIP1, MRE11A, NBN, RAD50, RAD51C, and RAD51D are genes involved in the Fanconi anemia (FA)-BRCA pathway, critical for DNA repair by homologous recombination, and interact in vivo with BRCA1 and/or BRCA2.4,20,45  Mutations in these genes are associated with an increased risk for female breast cancer.45-47 The ovarian cancer risk associated with mutations in BRIP1, RAD51C, and RAD51D has been estimated to be up to 9%, 5-9% and 10-12%, respectively.11,21,47-49  It has been suggested that BARD1 is associated with an increased risk for ovarian cancer, and mutations in MRE11A, NBN, and RAD50 have also been reported in at least one identified case of ovarian cancer to date.18,50  BRIP1, NBN, and RAD51C are each associated with a rare autosomal recessive disorder that affects multiple body systems.     

BMPR1A and SMAD4 are genes implicated in juvenile polyposis syndrome (JPS), together accounting for 45-60% of JPS. JPS is an autosomal dominant disorder that predisposes to the development of polyps in the gastrointestinal tract.51 Malignant transformation can occur; risk of gastrointestinal cancer ranges from 40-50%. Juvenile polyposis of infancy, which is rare, involves the entire digestive tract and has the poorest prognosis.52  Most patients develop symptoms by age 20, though some are not diagnosed until the third decade of life. Common symptoms include gastrointestinal bleeding, anemia, diarrhea, and abdominal pain. Early detection of JPS allows for better treatment of polyps and surveillance for those at risk. SMAD4 mutations may cause a combined syndrome of hereditary hemorrhagic telangiectasia (HHT) with JPS, as reported in 15-20% of JPS patients with SMAD4 mutations.53

CHEK2 is a gene that receives signals from damaged DNA, transmitted via ATMCHEK2 interacts in vivo with BRCA1, BRCA2, and TP53, which have all been implicated in cellular processes responsible for the maintenance of genomic stability. Multiple studies indicate that mutations in CHEK2 confer an increased risk of developing many types of cancer including breast, colon, and other cancers. Mutations are more likely to be found among women with bilateral versus unilateral breast cancers. A female CHEK2 mutation carrier has approximately a two-fold increase in lifetime breast cancer risk, and has a 1% risk per year of developing a second breast primary cancer. Lifetime risks for other associated cancers are unknown.  An increased risk for ovarian cancer has also been suggested.18,54-56

CDH1 germline mutations are associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancer in women. In one published study, the estimated cumulative risk of gastric cancer for CDH1 mutation carriers by age 80 years was 67% for men and 83% for women.57  Patients with HDGC typically present with diffuse-type gastric cancer, with signet ring cells diffusely infiltrating the wall of the stomach and, at advanced stages, linitis plastica. An elevated risk of lobular breast cancer in women is also associated with HDGC, with an estimated lifetime breast cancer risk of 39-52%.58

CDK4 is one of the genes associated with cutaneous malignant melanoma (CMM) syndrome. Individuals with CDK4 mutations demonstrate a higher frequency of atypical nevi, an earlier age of melanoma diagnosis (mean age 32-39 years), and an increased likelihood for multiple primary melanomas, as compared to individuals without CDK4 mutations.59,60  It is estimated that CDK4 mutation carriers have up to a 74% lifetime risk for malignant melanoma by age 50.59

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.61-63 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.64-66 Rare mutations that affect the p14ARF mutations have also been reported to predispose to melanoma and possibly pancreatic cancer.65,67,68

GREM1 A large duplication upstream of GREM1 has been identified families of Ashkenazi Jewish descent with hereditary mixed polyposis. To date, only this founder mutation has been reported, but the possibility of GREM1 mutations in individuals of other ethnicities has not been excluded.69 Manifestations of the GREM1 duplication appear to be limited to the intestinal tract, and include mixed morphology colon polyps and cancer; however, lifetime risk estimates for mutation carriers are not currently available.69,70

MLH1, MSH2, MSH6, PMS2, and EPCAM 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), and ovarian cancer (4-12% lifetime risk in women). 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.71-75

MUTYH germline mutations are known to cause MUTYH-associated polyposis (MAP), an autosomal recessive condition predisposing to gastrointestinal polyposis and colorectal cancer. Individuals that carry two MUTYH mutations on different chromosomes (in trans) have an estimated lifetime colorectal cancer risk of up to 80%.76  In addition, some studies suggest that MUTYH mutations confer an increased risk to develop female breast cancer; this is estimated to be a 1.5-fold lifetime increased risk within the North African Jewish population. MUTYH mutations in the carrier state may also increase lifetime risks for cancers of the duodenum, stomach, and endometrium;77-79 however, these data are limited and risks may vary between populations. Two common mutations in the Caucasian population, p.Y179C and p.G396D (originally designated as p.Y165C and p.G382D), account for the majority of pathogenic MUTYH alterations reported to date. Breast cancer risk estimates for male MUTYH mutation carriers are not currently available.

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. In addition, individuals with NF1 have an estimated lifetime risk for PGLs and PCCs of up to 7%.

PALB2 germline mutations have been associated with an increased lifetime risk for pancreatic cancer, breast cancer, and Fanconi anemia type N (FA-N). Familial pancreatic and/or breast cancer due to PALB2 mutations is inherited in an autosomal dominant pattern, while FA-N is a rare autosomal recessive condition affecting multiple body systems. Females with a PALB2 mutation have a 2- to 4-fold increase in risk for breast cancer.80,81  A 2014 article concluded that in the context of a strong family history, mutations in PALB2 may be associated with up to a 58% risk of female breast cancer.  Without a family history, the risk for female breast cancer was estimated to be 33% (the difference attributed to genetic and/or environmental modifiers).82 Studies have identified PALB2 mutations in 1-3% of families with pancreatic cancer; however, the exact lifetime pancreatic cancer risk has not yet been established.83,84  Additionally, recent studies have shown an increased risk for ovarian cancer.18,50

POLD1 and POLE mutations are implicated in an emerging syndrome of colorectal cancer and polyposis, called polymerase proofreading-associated polyposis (PPAP) by some.85 Exact cancer risks for mutation carriers have not yet been determined; however, published studies support POLD1 and POLE mutations as highly penetrant, conferring increased risk for early-onset colorectal cancer and/or multiple adenomas.86,87 Associations between POLD1 and POLE mutations and elevated incidence of extra-intestinal tumors have been suggested, although data is currently limited.

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.88,89 Recent studies noted increased risks for renal cell cancer, colorectal cancer, and other cancers.90,91 One study quotes up to a 31-fold increase in RCC risk for PTEN mutation carriers as compared to the general population.92  

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.93-96

STK11 germline mutations are associated with Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder characterized by the development of gastrointestinal hamartomatous polyps, along with hyperpigmentation of the skin and mucous membranes. Overall, individuals affected with PJS have up to an 85% lifetime risk of developing cancer by the age of 70, with gastrointestinal and breast cancers being the most common.97,98  Individuals with PJS are also at elevated risk for tumors of the pancreas, lung, and, in females, ovarian tumors, specifically, sex cord tumors with annular tubules (SCTATs) and mucinous ovarian tumors.

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%.99  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.12,100 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 TP53.56,101,102

Additional genes found on CancerNext-Expanded

The following genes are included in CancerNext-Expanded, but not in CancerNext:

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.103 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.103,104  Compared to AIP mutation-negative individuals with pituitary adenomas, individuals with mutations are more likely to have aggressive disease and present earlier in life.103 The median age of diagnosis of AIP-related FIPA is 23 years and penetrance estimates range from 33-66%.103,105

ALK heterozygous germline mutations in the ALK gene are associated with familial predisposition to neuroblastic tumors including neuroblastoma, ganglioneuroblastoma, and ganglioneuroma.106 Germline mutations in ALK have also been implicated in medulloblastoma risk, but further study is necessary.107 Penetrance for neuroblastoma is variable, and is estimated to be up to 57% across studies.108

BAP1 mutations have been shown to cause a tumor predisposition syndrome characterized by uveal melanoma, cutaneous melanoma, renal cell carcinoma, asbestos exposure-induced mesothelioma, and nonmalignant melanocytic BAP1-mutated atypical intradermal tumors (MBAITs).109-112 Lifetime cancer risks are increased, but are not well defined.

BLM is a gene associated with Bloom syndrome, a rare autosomal recessive condition affecting multiple body systems. Studies have demonstrated an increased risk for breast cancer in women who carry a Slavic founder mutation (p.Q548*) in BLM, including a meta-analysis of BLM mutations that suggested a two- to five-fold increased risk for female breast cancer in carriers.113,114  Additionally, BLM mutations have also been associated with an increased risk for colorectal cancer; however, exact cancer risks are not currently available.115,116

CDKN1B Heterozygous germline alterations are associated with multiple endocrine neoplasia type 4 (MEN4), characterized by parathyroid, anterior pituitary, and neuroendocrine tumors.117 Nearly 100% individuals with CDKN1B mutations develop hyperparathyroidism, however, penetrance estimates for other features of this syndrome are not currently available.118 MEN4 and multiple endocrine neoplasia type 1 share similar phenotypes, and mutations in CDKN1B account for 1-3% of individuals with clinically diagnosed MEN1 lacking a germline mutation in the MEN1 gene.117,119

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.120-122

FANCC is a gene involved in the Fanconi anemia pathway, critical for DNA repair by homologous recombination. Carriers of FANCC mutations have been identified in high-risk breast cancer families.123 A study found an increased risk for breast cancer in female relatives of patients with Fanconi anemia type C (FA-C) who carried a FANCC mutation.124 Other studies have identified FANCC mutations in patients with apparently sporadic, early-onset pancreatic cancer.125-127 Lifetime cancer risk estimates are not currently available for mutation carriers.

FH is a gene associated with hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is characterized by an increased lifetime risk of developing papillary type 2 renal tumors, with a lifetime risk of up to 20% for renal cancer and nearly 98% risk of cutaneous and uterine leiomyomas/fibroids.129 HLRCC-associated renal tumors are more likely to present as unilateral solitary lesions, with about 20% of individuals identified in their forties at an age range of 17-75 years. Almost all female HLRCC mutation carriers have uterine fibroids, with a mean age of diagnosis at 30 years, and an age range of 18-52 years.16,22,128,129  Although uterine fibroids are common in the general population, the fibroids in women with HLRCC tend to be larger and more numerous.  In addition, mutations in the FH gene have recently been reported in individuals with malignant pheochromocytomas (PCCs) and paragangliomas (PGLs).130,131

FLCN gene mutations cause Birt-Hogg-Dubé (BHD), an autosomal dominant hereditary renal cancer syndrome. A classic triad of findings characterizes BHD, which includes cutaneous fibrofolliculomas (benign skin tumors), pulmonary cysts, and renal tumors.16,132 Pulmonary cysts are found in approximately 80% of affected individuals, while bilateral renal tumors affect up to 34% of individuals. Secondary clinical findings can include spontaneous pneumothoraces, colorectal adenomas, parathyroid adenomas, neural tissue tumors, lipomas, angiolipomas, and connective tissue abnormalities. Individuals with BHD have about a 34% lifetime risk for renal cancer, most frequently diagnosed in the fifties.132-134 Additionally, male FLCN mutation carriers are twice as likely to be affected as female carriers.135,136 Approximately 50% of BHD-related renal tumors manifest as a chromophobe/oncocytic hybrid: 34% chromophobe, 9% clear cell, 5% oncocytoma, and 2% papillary.137

GALNT12 mutations have been identified in individuals with colorectal cancer and polyps. Carriers of GALNT12 mutations may be at an increased lifetime risk for colorectal cancer; however, lifetime cancer risk estimates are not currently available.138,139

HOXB13 encodes a transcription factor involved in epidermal differentiation and prostate gland development. Multiple studies have associated a recurrent HOXB13 mutation, p.G84E, with an increased risk for early-onset prostate cancer, however, lifetime cancer risk estimates are not currently available for mutation carriers.140-142  Data are insufficient to support increased cancer risks for other HOXB13 alterations at this time.

MAX is a tumor suppressor gene associated with PCC susceptibility. In one study of twelve MAX mutation carriers with PCC, 25% of patients showed metastasis, suggesting that, similar to SDHBMAX mutations are associated with an increased metastatic potential.143  The exact PCC lifetime risk is not yet established for MAX mutation carriers. Seemingly sporadic PCCs may be due to paternal transmission of the mutant allele.24,26,143

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.144  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.145-150 The majority of patients (94%) carrying a mutation in the MEN1 gene exhibit clinical or biochemical symptoms by age 50.151

MET is a proto-oncogene associated with hereditary papillary renal carcinoma (HPRC). HPRC is an autosomal dominant disorder with high penetrance, characterized by increased risk for bilateral (or multifocal type 1) papillary renal cancer. HPRC-associated renal cancer has a median age of onset of 60-80 years.16,17,129  Furthermore, HPRC renal tumors show frequent somatic trisomy of chromosome 7, and earlier-onset carcinoma can be attributed to germline missense mutations in the tyrosine kinase domain of the MET proto-oncogene.152

MITF is a gene implicated in melanoma and renal cell carcinoma (RCC) development pathways.153,154  As such, MITF mutation carriers have an increased predisposition to developing melanoma and/or RCC. A specific mutation with unique functional consequences, p.E318K, has been detected at increased frequency in both melanoma and RCC cohorts.153,154  MITF mutation carriers are estimated to have a 2-8 fold increased risk for melanoma and a 5-fold increased risk for RCC as compared to the general population.153,155

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%).156  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.157

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.158 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.159 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.160

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.161,162  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%).163-166

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 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.167-171  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.

RET is a proto-oncogene associated with multiple endocrine neoplasia type 2 (MEN2). MEN2 is an autosomal dominant disorder characterized by the presence of benign or malignant endocrine system tumors. MEN2 is divided into three clinical subtypes: MEN2A (>90% of patients), MEN2B, and familial medullary thyroid carcinoma (FMTC). MEN2-associated PCCs are often multifocal and bilateral, with a median age of diagnosis between 30-40 years.24,26,172

RB1 encodes a 928 amino acid nuclear phosphoprotein pRB, which functions as a negative regulator of the cell cycle and cell proliferation. Heterozygous pathogenic mutations in RB1 cause retinoblastoma, a malignant tumor of the developing retina. Individuals with germline mutations in RB1 typically present with bilateral tumors, though some individuals develop unilateral or trilateral (involving the pineal gland) disease. The majority of mutations is highly penetrant and confers a 90% risk for retinoblastoma.173  However, a subset of mutations is moderately penetrant and result in lower and variable risk of disease.174  Individuals with hereditary retinoblastoma are at increased risk to develop second primary malignancies including osteosarcomas, soft tissue sarcomas, and melanoma, as well as other common epithelial malignancies. Risks for such malignancies vary based on laterality of tumor, family history, age at initial diagnosis, and treatment course.175,176

SDHA, SDHB, SDHC, SDHD, and SDHAF2 are all genes associated with hereditary paraganglioma and pheochromocytoma (PGL/PCC) syndrome. Germline mutations in these genes have been associated with susceptibility to head and neck paragangliomas (HNPGLs), extra-adrenal PGLs/PCCs and, rarely, renal cell carcinoma (RCC) with gastrointestinal stromal tumors (Carney-Stratakis syndrome).177 SDHB associated RCC can be of varied histology with reported cases of clear cell, papillary, granular, and mixed.178,179  The exact lifetime risk for PCC is not yet established for SDHB mutation carriers.180  The SDHD and SDHAF2 genes are subject to the effects of imprinting (parent-of-origin effects), and cancer risk is correlated with paternal transmission.181-183 Mutations in the SDH genes have also been associated with PTEN mutation-negative Cowden syndrome.184

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.185 Age of onset and penetrance are extremely variable, with some carriers presenting at birth while others remain unaffected through adulthood.186  Approximately 5% of individuals with schwannomatosis due to SMARCB1 mutation also develop meningiomas.185 SMARCB1 mutations are thought to account for 35% of AT/RT, 48% of familial schwannomatosis, and 10% of sporadic schwannomatosis.185,186  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.185

SMARCE1 heterozygous loss-of-function alterations such as truncations, frameshifts, and gross deletions cause predisposition for multiple spinal and cranial clear cell meningiomas.187,188  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.188

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.189  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.190,191  Some individuals with mutations in SUFU develop isolated medulloblastoma without other symptoms of NBCCS.191 SUFU has also been implicated in familial meningioma.192

TMEM127 is a proposed tumor suppressor gene associated with PGL/PCC susceptibility.193 TMEM127 mutations demonstrate an autosomal dominant pattern of inheritance with unknown penetrance.24,26 TMEM127-associated PCCs can present bilaterally or unilaterally, and may also be found in patients with no family history of PCC.180,193  One study reported TMEM127 mutations in 2 of 48 patients with PGL.193

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.194  Benign hamartomas can be found in the heart (rhabdomyomas), brain (astrocytomas), kidneys (angiomyolipomas), skin, eyes, lungs (pulmonary lymphangioleimyomatosis), skeleton, and endocrine glands.194-198  The lifetime risk of renal cancer development in TSC is 2-5%.195

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 rate and an estimated incidence of 1 in 36,000.129   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.199  Published literature supports that patients carrying a partial germline VHL gene deletion have a higher RCC risk than those carrying full-gene deletions.17,129

XRCC2 is a gene involved in the Fanconi anemia pathway, critical for DNA repair by homologous recombination. Female and male individuals with breast cancer have been found to carry monoallelic mutations in XRCC2.200-202 Currently, breast cancer lifetime risk estimates are not available for mutation carriers.

Testing Benefits & Indication 

Indications for Testing

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

  • A family history clearly suggestive of hereditary cancer, but all normal genetic testing results thus far 
  • Several different types of cancers in the family history that do not seem to fit a particular hereditary cancer syndrome
  • A family history pattern with features of several hereditary cancer syndromes

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 (for example colon and uterine cancer in Lynch syndrome, or breast and pancreatic cancer with PALB2 mutations) 

*On the same side of the family 

If increased risk of a hereditary cancer syndrome is suspected, the American Congress (formerly College) of Obstetricians and Gynecologists (ACOG) recommends referral to a specialist in cancer genetics or a healthcare provider with expertise in genetics for complete hereditary cancer risk assessment, which may lead to genetic testing.140 Establishing a molecular diagnosis can help guide preventive measures, direct surgical options and estimate personal and familial cancer risk. 

Benefits of Testing
Identifying patients with an inherited susceptibility for certain cancers can help with medical management. For example, this information can:

  • Modify cancer surveillance options and age of initial screening
  • Suggest specific risk-reduction measures (e.g. considering prophylactic oophorectomy, after childbearing is complete, for women with increased risk for breast/ovarian cancer)
  • Clarify and stratify familial cancer risks, based on gene-specific cancer associations, such as risk for uterine, colon, and ovarian cancer with MLH1 mutations
  • Offer treatment guidance (e.g. avoidance of radiation-based treatment methods for individuals with a TP53 mutation)
  • Identify other at-risk family members
  • Provide guidance with new gene-specific treatment options and risk reduction measures as they emerge
Test Description 

CancerNext-Expanded analyzes 67 genes (listed above). 65 genes (excluding EPCAM and GREM1) 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). For POLD1 and POLE, missense variants located outside of the exonuclease domains (codons 311-541 and 269-485, respectively) are not routinely reported. For MITF, only the status of the c.952G>A (p.E318K) alteration is analyzed and reported. The inversion of coding exons 1-7 of the MSH2 gene and the BRCA2 Portuguese founder mutation, c.156_157insAlu (also known as 384insAlu) are 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.203  Gross deletion/duplication analysis is performed for the covered exons and untranslated regions of 66 genes (excluding MITF) using read-depth from NGS data with confirmatory multiplex ligation-dependent probe amplification (MLPA) and/or targeted chromosomal microarray. For GREM1, only the status of the 40kb 5’ UTR gross duplication is analyzed and reported. 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 

CancerNext-Expanded 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 
8874 CancerNext-Expanded 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]. Available from:
  3. Castera L, et al. Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes. Eur J Hum Genet. 2014. 22(11):1305-13.
  4.  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.
  5. van der Groep P, van der Wall E, van Diest PJ. Pathology of hereditary breast cancer. Cell Oncol (Dordr). 2011. 34(2):71-88.
  6. Walsh T and King MC. Ten genes for inherited breast cancer. Cancer Cell. 2007. 11(2):103-5.
  7. Meindl A, et al. Hereditary breast and ovarian cancer: new genes, new treatments, new concepts. Dtsch Arztebl Int. 2011. 108(19):323-30.
  8. Antoniou A, et al. Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: a combined analysis of 22 studies. Am J Hum Genet. 2003. 72(5):1117-30.
  9. Chen S and Parmigiani G. Meta-analysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007. 25(11):1329-33.
  10. Ford D, et al. Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. The Breast Cancer Linkage Consortium. Am J Hum Genet. 1998. 62(3):676-89.
  11. Loveday C, et al., Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet. 2012. 44(5):475-6; Author reply 476.
  12. 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.
  13. Hampel H. Genetic testing for hereditary colorectal cancer. Surg Oncol Clin N Am. 2009. 18(4):687-703.
  14. Rosner I, et al. The clinical implications of the genetics of renal cell carcinoma. Urol Oncol. 2009. 27(2):131-6.
  15. Chan-Smutko G. Genetic testing by cancer site: urinary tract. Cancer J. 2012. 18(4):343-9.
  16. Coleman JA and Russo P. Hereditary and familial kidney cancer. Curr Opin Urol. 2009. 19(5):478-85.
  17. Rini BI, Campbell SC, Rathmell WK. Renal cell carcinoma. Curr Opin Oncol. 2006. 18(3):289-96.
  18. Walsh T, et al. Mutations in 12 genes for inherited ovarian, Fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011. 108(44):18032-7.
  19. Pennington KP, et al. Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, Fallopian tube, and peritoneal carcinomas. Clin Cancer Res. 2014. 20(3):764-75.
  20. Pennington KP and Swisher EM. Hereditary ovarian cancer: beyond the usual suspects. Gynecol Oncol. 2012. 124(2):347-53.
  21. Loveday C, et al., Germline RAD51C mutations confer susceptibility to ovarian cancer. Nat Genet. 2012. 44(5):475-6; Author reply 476.
  22. Loveday C, et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet. 2011. 43(9):879-82.
  23. Shi C. Hruban RH, Klein AP. Familial pancreatic cancer. Arch Pathol Lab Med. 2009. 133(3):365-74.
  24. Fishbein L and Nathanson KL. Pheochromocytoma and paraganglioma: understanding the complexities of the genetic background. Cancer Genet. 2012. 205(1-2):1-11.
  25. Welander J, Soderkvist P, Gimm O. Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocr Relat Cancer 2011. 18(6):R253-76.
  26. DeLellis RA. Pathology and genetics of tumours of endocrine organs. World Health Organization classification of tumours. 2004, Lyon, France: IARC Press.
  27. Fishbein L, et al. Inherited mutations in pheochromocytoma and paraganglioma: why all patients should be offered genetic testing. Ann Surg Oncol. 2013. 20(5):1444-50.
  28. Mannelli M, et al. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. J Clin Endocrinol Metab. 2009. 94(5):1541-7.
  29. Mannelli M, et al. Subclinical phaeochromocytoma. Best Pract Res Clin Endocrinol Metab. 2012. 26(4):507-15.
  30. Castro E, et al. Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer. J Clin Oncol. 2013 May 10;31(14):1748-57.
  31. Lipton L and Tomlinson I. The genetics of FAP and FAP-like syndromes. Fam Cancer. 2006. 5(3):221-6.
  32. Petersen GM, Slack J, Nakamura Y. Screening guidelines and premorbid diagnosis of familial adenomatous polyposis using linkage. Gastroenterology. 1991. 100(6):1658-64.
  33. 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.
  34. Renwick A, et alATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles. Nat Genet. 2006. 38(8):873-5.
  35. Roberts NJ, et alATM mutations in patients with hereditary pancreatic cancer. Cancer Discovery. 2011. 2(1):OF1-OF6.
  36. Janavicius R. Founder BRCA1/2 mutations in Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010. 1(3):397-412.
  37. Ferla R, et al. Founder mutations in BRCA1 and BRCA2 genes. Ann Oncol. 2007. 18 Suppl 6:vi93-8.
  38. Tulinius H, et al. The effect of a single BRCA2 mutation on cancer in Iceland. J Med Genet. 2002. 39(7):457-62.
  39. Tai YC, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007. 99(23):1811-4.
  40. Thompson D, et al. Breast cancer linkage, cancer incidence in BRCA1 mutation carriers. J Natl Cancer Inst. 2002. 94(18):1358-65
  41. Folkins AK and Longacre TA. Hereditary gynaecological malignancies: advances in screening and treatment. Histopathology. 2013. 62(1):2-30.
  42. Shannon KM and Chittenden A. Genetic testing by cancer site: breast. Cancer J. 2012. 18(4):310-9.
  43. Kote-Jarai Z, et alBRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011. 105(8):1230-4.
  44. van Asperen CJ, et al. Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet. 2005. 42(9):711-9.
  45. Damiola  F, et al. Rare key functional domain missense substitutions in MRE11ARAD50, 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.
  46. Seal S, et al. Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles. Nat Genet. 2006. 38(11):1239-41.
  47. Meindl A, et al. Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet. 2010. 42(5):410-4.
  48. Song et al. Contribution of germline mutations in the RAD51B, RAD51C, and RAD51D genes to ovarian cancer in the population. J Clin Oncol. 2015. 33 (26): 2901-7.
  49. 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).
  50. Norquist BM, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016 Apr;2(4):482-90.
  51. van Hattem WA, et al. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut. 2008. 57(5):623-7.
  52. Chow E and Macrae F. A review of juvenile polyposis syndrome. J Gastroenterol Hepatol. 2005. 20(11):1634-40.
  53. Gallione CJ, et al. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4)Lancet. 2004. 363(9412):852-9.
  54. Bahassi EM, et al. The checkpoint kinases Chk1 and Chk2 regulate the functional associations between hBRCA2 and Rad51 in response to DNA damage. Oncogene. 2008. 27(28):3977-85.
  55. Cybulski C, et alCHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet. 2004. 75(6):1131-5.
  56. 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.
  57. Pharoah PD, et al. Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology 2001. 121(6):1348-53.
  58. Guilford P, Humar B, Blair V. Hereditary diffuse gastric cancer: translation of CDH1 germline mutations into clinical practice. Gastric Cancer. 2010. 13(1):1-10.
  59. Goldstein AM, et al. High-risk melanoma susceptibility genes and pancreatic cancer, neural system tumors, and uveal melanoma across GenoMEL. Cancer Res. 2006. 66(20):9818-28.
  60. Puntervoll, HE, et al. Melanoma prone families with CDK4 germline mutation: phenotypic profile and associations with MC1R variants. J Med Genet. 2013. 50(4):264-70.
  61. 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.
  62. Bishop DT, et al. Geographical variation in the penetrance of CDKN2A mutations for melanoma. J Natl Cancer Inst. 2002. 94(12):894-903.
  63. 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.
  64. 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.
  65. 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.
  66. 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.
  67. 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.
  68. Binni F, et al. Novel and recurrent p14 mutations in Italian familial melanoma. Clin Genet. 2010. 77(6):581-6.
  69. Jaeger E, et al. Hereditary mixed polyposis syndrome is caused by a 40-kb upstream duplication that leads to increased and ectopic expression of the BMP antagonist GREM1Nat Genet. 2012;44(6):699-703.
  70. Davis H, et al. Aberrant epithelial GREM1 expression initiates colonic tumorigenesis from cells outside the stem cell niche. Nature Medicine. 2015;21(1):62-70. Epub December 1, 2014.
  71. 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.
  72. 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.
  73. Bonadona V, et al. Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6genes in Lynch syndrome. JAMA. 2011. 305(22):2304-10.
  74. Engel C, et al. Risks of less common cancers in proven mutation carriers with Lynch syndrome. J Clin Oncol. 2012. 30(35):4409-15.
  75. 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
  76. Jenkins MA, et al. Risk of colorectal cancer in monoallelic and biallelic carriers of MYH mutations: a population-based case-family study. Cancer Epidemiol Biomarkers Prev. 2006. 15(2):312-4.
  77. Win AK, et al. Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer. Int J Cancer. 2011. 129(9):2256-62.
  78. Vogt S, et al. Expanded extracolonic tumor spectrum in MUTYH-associated polyposis. Gastroenterology. 2009. 137(6):1976-85 e1-10.
  79. Rennert G, et alMutYH mutation carriers have increased breast cancer risk. Cancer. 2012. 118(8):1989-93.
  80. Slater EP, et alPALB2 mutations in European familial pancreatic cancer families. Clin Genet. 2010. 78(5):490-4.
  81. Casadei S, et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011. 71(6):2222-9.
  82. Antoniou AC, et al. Breast-cancer risk in families with mutations in PALB2N Engl J Med. 2014. 371(6):497-506.
  83. Tischkowitz MD, et al. Analysis of the gene coding for the BRCA2-interacting protein PALB2 in familial and sporadic pancreatic cancer. Gastroenterology. 2009. 137(3):1183-6.
  84. Jones S, et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009. 324(5924):217.
  85. Church JM. Polymerase Proofreading-associated polyposis: A new, dominantly inherited syndrome of hereditary colorectal cancer predisposition. Diseases of the colon and rectum. 2014;57(3):396-7.
  86. Palles C, et al. Germline mutations in the proof-reading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas. Nat Genet. 2013;45(2):136-44.
  87. Valle L, et al. New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis. Hum Mol Gen. 2014 Jul 1;23(13):3506-12.
  88. Eng C. Will the real Cowden syndrome please stand up: revised diagnostic criteria. J Med Genet 2000. 37(11):828-30.
  89. Starink TM, et al. The Cowden syndrome: a clinical and genetic study in 21 patients. Clin Genet. 1986. 29(3):222-33.
  90. Heald B, et al. Frequent gastrointestinal polyps and colorectal adenocarcinomas in a prospective series of PTEN mutation carriers. Gastroenterology. 2010. 139(6):1927-33.
  91. Tan MH, et al. Lifetime cancer risks in individuals with germline PTEN mutations. Clin Cancer Res. 2012. 18(2):400-7.
  92. Mester JL, et al. Papillary renal cell carcinoma is associated with PTEN hamartoma tumor syndrome. Urology. 2012. 79(5):1187 e1-7.
  93. 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
  94. 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.
  95. 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.
  96. 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.
  97. Hearle N, et al. Frequency and spectrum of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res. 2006. 12(10):3209-15.
  98. Lim W, et al. Relative frequency and morphology of cancers in STK11 mutation carriers. Gastroenterology. 2004. 126(7):1788-1794.
  99. 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.
  100. 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.
  101. Gonzalez KD, et al. Beyond Li-Fraumeni syndrome: clinical characteristics of families with p53germline mutations. J Clin Oncol. 2009. 27(8):1250-6.
  102. McCuaig JM, et al. Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer. 2012. 11(4):607-13.
  103. 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.
  104. Beckers A and Daly AF. The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol. 2007 Oct;157(4):371-82.
  105. 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.
  106. 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.
  107. Coco S, et al. Identification of ALK germline mutation (3605delG) in pediatric anaplastic medulloblastoma. J Hum Genet. 2012 Oct;57(10)682-4.
  108. Eng C. Cancer: A ringleader identified. Nature. 2008 Oct 16:455(7215):883-4.
  109. Pilarski R, et al. Expanding the clinical phenotype of hereditary BAP1 cancer predisposition syndrome, reporting three new cases. Genes Chromosomes Cancer. 2014;53:177-82.
  110. Popova T, et al. Germline BAP1 mutations predispose to renal cell carcinomas. Am J Hum Genet. 2013;92:974-80.
  111. Testa JR, et al. Germline BAP1 mutations predispose to malignant mesothelioma. Nat Genet. 2011;43(10):1022-5.
  112. Wiesner T, et al. Germline mutations in BAP1 predispose to melanocytic tumors. Nat Genet. 2011;43(10):1018-21.
  113. Sokolenko AP, et al. High prevalence and breast cancer predisposing role of the BLM c.1642C>T (Q548X) mutation in Russia. Int J Cancer. 2012. 130(12):2867-73.
  114. 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.
  115. Gruber SB, et al. BLM heterozygosity and the risk of colorectal cancer. Science. 2002. 297(5589):2013.
  116. de Voer RM, et al. Deleterious germline BLM mutations and the risk for early-onset colorectal cancer. Sci Rep. 2015. 5:14060.
  117. 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.
  118. 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.
  119. 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.
  120. 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.
  121. 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.
  122. de Kock L, et al. Pituitary blastoma: a pathognomonic feature of germline DICER1 mutations. Acta Neuropathol. 2014. 128(1):111-22.
  123. Thompson ER, et al. Exome sequencing identifies rare deleterious DNA repair genes FANCC and BLM as potential breast cancer susceptibility alleles. PLos Genet. 2012. 8(9):e1002894
  124. Berwick M, et al. Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer. Cancer Res. 2007. 67(19):9591-6.
  125. van der Heijden MS, et al. Fanconi anemia gene mutations in young-onset pancreatic cancer. Cancer Res. 2003. 65(10):2585-8.
  126. Rogers CD, et al. The genetics of FANCC and FANCG in familial pancreatic cancer. Cancer Biol Ther. 2004. 3(2):167-9.
  127. Couch FJ, et al. Germline Fanconi anemia complementation group C mutations and pancreatic cancer. Cancer Res. 2005. 65(2):383-6.
  128. Gardie B, et al. Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma. J Med Genet. 2011. 48(4):226-34.
  129. Barrisford GW, et al. Familial renal cancer: molecular genetics and surgical management. Int J Surg Oncol. 2011. 2011:658767.
  130. Castro-Vega LJ, et al. Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23(9):2440-6. 
  131. Clark GR, et al. Germline FH mutations presenting with pheochromocytoma. J Clin Endocrinol Metab. 2014;99(10):E2046-50. 
  132. Baba M, et al. Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A. 2006. 103(42):15552-7.
  133. Pavlovich CP, et al. Evaluation and management of renal tumors in the Birt-Hogg-Dubé syndrome. J Urol. 2005. 173(5):1482-6.
  134. Schmidt LS, et al. Germline BHD-mutation spectrum and phenotype analysis of a large cohort of families with Birt-Hogg-Dubé syndrome. Am J Hum Genet. 2005. 76(6):1023-33.
  135. Lim DH, et al. A new locus-specific database (LSDB) for mutations in the folliculin (FLCN) gene. Hum Mutat. 2010. 31(1):E1043-51.
  136. Zbar B, et al. Risk of renal and colonic neoplasms and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer Epidemiol Biomarkers Prev. 2002. 11(4):393-400.
  137. Vocke CD, et al. High frequency of somatic frameshift BHD gene mutations in Birt-Hogg-Dubé-associated renal tumors. J Natl Cancer Inst. 2005. 97(12):931-5.
  138. Guda K, et al. Inactivating germline and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. Proc Natl Acad Sci U.S.A. 2009. 106(31):12921-5.
  139. Clarke E, et al. Inherited deleterious variants in GALNT12 are associated with CRC susceptibility. Hum Mutat. 2012. 33(7):1056-8.
  140. Ewing CM, et al. Germline mutations in HOXB13 and prostate cancer risk. N Engl J Med. 2012. 366(2):141-9.
  141. Lin X, et al. A novel germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men. Prostate. 2013. 73(2):169-75.
  142. Maia S, et al. Identification of two novel HOXB13 germline mutations in Portuguese prostate cancer patients. PLoS One. 2015. 10(7):e0132728.
  143. Comino-Mendez I, et al. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet. 2011. 43(7):663-7.
  144. Hannan FM, et al. Familial isolated primary hyperparathyroidism caused by mutations of the MEN1 gene. Nat Clin Prac End Metab. 2008;4(1):53-8
  145. 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.
  146. Thakker RV, et al. Clinical practice guidelines for multiple endocrine neoplasia type 1 (MEN1). J Clin Endocrinol Metab. 2012;97(2990-3011):2990.
  147. Carty SE, et al. The variable penetrance and spectrum of manifestations of multiple endocrine neoplasia type 1. Surgery. 1998;124(6):1106-14.
  148. 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.
  149. Marx SJ, et al. Multiple endocrine neoplasia type 1: clinical and genetic topics. Ann Intern Med. 1998;129:484-94.
  150. 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.
  151. Chandrasekharappa SC, et al. Positional cloning of the gene for multiple endocrine neoplasia–type 1. Science. 1997;276:404-7.
  152. Schmidt L, et al. Two North American families with hereditary papillary renal carcinoma and identical novel mutations in the MET proto-oncogene. Cancer Res. 1998;58(8):1719-22. 
  153. Bertolotto C, et al. A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma. Nature. 2011. 480(7375):94-8.
  154. Yokoyama S, et al. A novel recurrent mutation in MITF predisposes to familial and sporadic melanoma. Nature. 2011. 480(7375):99-103.
  155. Potrony M, et al. Prevalence of MITF p.E318K in patients with melanoma independent of the presence of CDKN2A causative mutations. JAMA Dermatol. 2016. 152(4):405-12.
  156. Asthagiri AR, et al. Neurofibromatosis type 2. Lancet. 2009 Jun 6;373(9679:1974-86.
  157. Petrilli AM, et al. Role of Merlin/NF2 inactivation in tumor biology. Oncogene. 2016, 35(5): 537-548
  158. 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.
  159. 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.
  160. 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.
  161. 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.
  162. Jones S, et al. Personalized genomic analyses for cancer mutation discovery and interpretation. Sci Transl Med. 2015 Apr 15;7(283):283ra53.
  163. 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
  164. 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.
  165. Mateus C, et al. Heterogeneity of skin manifestations in patients with Carney complex. J Am Acad Dermatol. 2008 Nov;59(5):801-10.
  166. 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.
  167. 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.
  168. 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.
  169. Joshi PS, et al. Gorlin-Goltz syndrome. Dent Res J (Isfahan). 2012;9(1):100-106.
  170. Li TJ, et alPTCH germline mutations in Chinese nevoid basal cell carcinoma syndrome patients. Oral Dis. 2008;14(2):174-179.
  171. 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.
  172. Eng C, et al. The relationship between specific RET proto-oncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA. 1996. 276(19):1575-9.
  173. Lohmann DR, et al. The spectrum of RB1 germline mutations in hereditary retinoblastoma. Am J Hum Genet. 1996;58(5):940-9. 
  174. Harbour JW. Molecular basis of low-penetrance retinoblastoma. Arch Ophthalmol. 2001;119(11):1699-704.
  175. Kleinerman RA, et al. Variation of second cancer risk by family history of retinoblastoma among long-term survivors. J Clin Oncol. 2012;30(9):950-7.
  176. Wong JR, et al. Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol. 2014;32(29):3284-90.
  177. Carney JA and Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet. 2002. 108(2):132-9.
  178. Ricketts C, et al. Germline SDHB mutations and familial renal cell carcinoma. J Natl Cancer Inst. 2008. 100(17):1260-2.
  179. Vanharanta S, et al. Early-onset renal cell carcinoma as a novel extraparaganglial component of SDHB-associated heritable paraganglioma. Am J Hum Genet. 2004. 74(1):153-9.
  180. Ricketts CJ, et al. Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHDHum Mutat. 2010. 31(1):41-51.
  181. Baysal BE. Mitochondrial complex II and genomic imprinting in inheritance of paraganglioma tumors. Biochim Biophys Acta. 2013. 1827(5):573-7.
  182. Hao HX, et alSDH5, a gene required for flavination of succinate dehydrogenase, is mutated in paraganglioma. Science. 2009. 325(5944):1139-42.
  183. Kunst HP, et alSDHAF2 (PGL2-SDH5) and hereditary head and neck paraganglioma. Clin Cancer Res. 2011. 17(2):247-54.
  184. Ni Y, et al. Germline mutations and variants in the succinate dehydrogenase genes in Cowden and Cowden-like syndromes. Am J Hum Genet. 2008. 83(2):261-8.
  185. Smith MJ, et al. SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors. Cancer Genet. 2014, 207(9): 373-378.
  186. Eaton KW et al. Spectrum of SMARCB1/INI1 mutations in familial and sporadic rhabdoid tumors. Pediatr Blood Cancer. 2011 Jan;56(1):7-15.
  187. 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.
  188. Smith, MJ et al. Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. J Pathol. 2014, 234(4): 436-440.
  189. Gorlin RJ. Nevoid basal cell carcinoma (Gorlin) syndrome. Genet Med. 2004 Nov-Dec;6(6):530-9.
  190. 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.
  191. 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.
  192. Aavikko M, et al. Loss of SUFU function in familial multiple meningioma. Am J Hum Genet. 2012 Sep 7;91(3):52-6.
  193. Neumann HP, et al. Germline mutations of the TMEM127 gene in patients with paraganglioma of head and neck and extraadrenal abdominal sites. J Clin Endocrinol Metab. 2011. 96(8):E1279-82.
  194. 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.
  195. Borkowska J, et al. Tuberous sclerosis complex: tumors and tumorigenesis. Int J Dermatol. 2011. 50(1):13-20.
  196. 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.
  197. Rodrigues DA, et al. Tuberous sclerosis complex. An Bras Dermatol. 2012. 87(2):184-96.
  198. 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.
  199. Lonser RR, et al. von Hippel-Lindau disease. Lancet. 2003. 361(9374):2059-67.
  200. Kuschel B, et al. Variants in DNA double-strand break repair genes and breast cancer susceptibility. Hum Mol Genet. 2002. 11(12):1399-407.
  201. Park DJ, et al. Rare mutations in XRCC2 increase the risk of breast cancer. Am J Hum Genet. 2012. 90(4):734-9.
  202. Couch FJ, et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015. 33(4):304-11.
  203. 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.