Test Information Sheet

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1 Test Information Sheet GeneDx 207 Perry Parkway Gaithersburg, MD Phone: Fax: OncoGeneDx: Breast Cancer High Risk Panel and PALB2 Gene List for the OncoGeneDx Breast Cancer High Risk Panel and PALB2: BRCA1 BRCA2 CDH1 PALB2 PTEN TP53 Clinical Features: In the general population, approximately 1 in 8 women (12%) will develop breast cancer in their lifetime (SEER). Most cases of breast cancer develop sporadically with no family history of the cancer; however, 5 10% of cases are thought to be due to a hereditary predisposition. The features suggestive of a hereditary cancer predisposition include: young age at diagnosis (before age 50), multiple primary cancers in a single individual, diagnosis of a cancer type that is not common in the general population (such as ovarian cancer, male breast cancer, or pancreatic cancer), and several relatives affected with related cancers spanning multiple generations. The OncoGeneDx Breast Cancer High Risk Panel and PALB2 includes genes associated with a defined increased level of breast cancer risk including those associated with hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2), hereditary diffuse gastric cancer syndrome (CDH1), PTEN hamartoma tumor syndrome (PTEN), Li Fraumeni syndrome (TP53) as well as PALB2. It is estimated that 20 25% of familial breast cancer risk can be attributed to pathogenic variants in the BRCA1 or BRCA2 genes (Easton 1999, Pharoah 2002, van der Groep 2011). The contribution of pathogenic variants in the CDH1, PTEN, TP53 and PALB2 genes to familial breast cancer risk overall is less well characterized but is considerably lower than the contribution of BRCA1 and BRCA2 pathogenic variants. Hereditary Breast and Ovarian Cancer syndrome (BRCA1 and BRCA2): Women with pathogenic variants in BRCA1 or BRCA2 have a 41 87% lifetime risk to develop breast cancer and an up to 63% risk for contralateral breast cancer (Antoniou 2003, Chen 2007, Claus 1996, Ford 1998, King 2003, Graeser 2009, Risch 2006). Studies have shown that the lifetime risk to develop ovarian cancer is between 24 54% for BRCA1 pathogenic variant carriers and 11 27% for BRCA2 pathogenic variant carriers (Antoniou 2003, Chen 2007, Ford 1998, King 2003, Risch 2006). Other cancers associated with pathogenic variants in BRCA1 and BRCA2 in women include fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron Shental 2006, Pennington 2013). The lifetime risk for breast cancer in male BRCA1/2 pathogenic variant carriers is approximately 7% with a pathogenic variant in BRCA2 and slightly increased with a pathogenic variant in BRCA1 (Liede 2004, Tai 2007). Other malignancies reported in families with pathogenic variants in BRCA1 or BRCA2 include prostate cancer in men, as well as pancreatic cancer and melanoma in both men and women. Hereditary diffuse gastric cancer syndrome (CDH1): Women with a pathogenic variant in CDH1 have a 39 52% lifetime risk for lobular breast cancer. The lifetime risk of diffuse gastric cancer has been estimated to be 40 67% for men and 63 83% for women (Kaurah 2007, Pharoah 2001). Diffuse gastric cancer generally occurs before age 50 in carriers of CDH1 pathogenic variants, and even cases under the age of 18 have been reported in families with hereditary diffuse gastric cancer (Guilford 1998). Signet ring cell cancer of the colon has also been reported in individuals with CDH1 pathogenic variants (Brooks Wilson 2004). Information Sheet on Breast Cancer High Risk Panel and PALB2 Page 1 of 5 GeneDx Revision Date: 07/2016

2 PTEN hamartoma tumor syndrome (PTEN): Cowden Syndrome (CS) and Bannayan Riley Ruvalcaba (BRRS) are two conditions belonging to the spectrum of PTEN hamartoma tumor syndrome (PHTS) and are associated with an increased risk of developing cancer. There is an approximate 25 45% risk for breast cancer and 5 10% risk for endometrial cancer in women, and 10% risk for non medullary thyroid cancer in women and men (Hobert 2009). Additional clinical features in CS include increased head circumference 97 th percentile (macrocephaly), trichilemmomas, papillomatous papules, and the pathognomonic finding of cerebellar dysplastic gangliocytoma (Lhermitte Duclos disease). CS may be also associated with benign breast disease, thyroid goiters, benign gastrointestinal polyps, and uterine fibroids. BRRS is associated with macrocephaly, intestinal hamartomas, pigmented macules of the glans penis, and can be associated with developmental delay or autism. Vascular abnormalities, such as hemangiomas and arterio venous malformations, have also been reported in individuals with pathogenic variants in PTEN. PALB2: Women with a pathogenic variant in PALB2 have been estimated to have a 2 to 3 fold increased risk of breast cancer over the general population (Erkko 2008, Rahman 2007) resulting in a lifetime risk of approximately 25% to 40%. More recent data has suggested a lifetime risk (up to age 70) ranging from 33% to 58% depending on the individual s family history of breast cancer (Antoniou 2014). Women with a pathogenic variant in PALB2 who have a family history of early onset breast cancer may have a lifetime risk up to 58% (Byrnes 2008, Antoniou 2014). Casadei et al. (2011) found that PALB2 pathogenic variant carriers are 6 fold more likely to have a family history of pancreatic cancer, 1.3 fold more likely to have a family history of ovarian cancer and 4 fold more likely to have a family history of male breast cancer. Although the association of pathogenic variants in PALB2 and pancreatic cancer has been established, the exact risks are not yet well understood (Jones 2009, Slater 2010). Li Fraumeni syndrome (TP53): The following core cancer types account for 70 77% of LFS associated tumors (in order of frequency): breast cancer, soft tissue sarcoma, brain tumors, osteosarcoma, and adrenocortical carcinoma (Gonzalez 2009, Olivier 2003, Ruijs 2010). Other types of cancer that may be associated with LFS include ovarian, gastrointestinal, pancreatic, genitourinary, skin, thyroid and lung cancers as well as leukemia, lymphoma, and neuroblastomas. Age related and sex specific cancer risks have been reported. Individuals with LFS who have been diagnosed with cancer have up to a 57% risk of developing a second primary cancer within 30 years of the first diagnosis and up to a 38% risk of a third primary diagnosis (Hisada 1998). Several studies have demonstrated that subsequent tumors often develop in the radiation field of the previously treated cancer (Chompret 2000, Hisada 1998). Specific cancer screening and prevention recommendations for individuals with pathogenic variants in all of the genes on this panel can be found in the NCCN Clinical Practice Guidelines in Oncology Genetic/Familial High Risk Assessment: Breast and Ovarian at The International Gastric Cancer Linkage Consortium has published updated consensus guidelines for the management of individuals with hereditary diffuse gastric cancer. The available medical management guidelines pertinent to each gene are listed in the attached table. Inheritance Pattern: Hereditary Breast and Ovarian Cancer syndrome (BRCA1 and BRCA2), hereditary diffuse gastric cancer syndrome (CDH1), Cowden syndrome/pten hamartoma tumor syndrome (PTEN), Li Fraumeni syndrome (TP53) and pathogenic variants in the PALB2 gene are inherited in an autosomal dominant manner. While de novo pathogenic variants in the BRCA1, BRCA2, and CDH1 genes are uncommon, PTEN and TP53 pathogenic variants have been shown to occur de novo in a subset of cases. At this time, the de novo pathogenic variant rate of PALB2 is unknown. Biallelic pathogenic variants in the BRCA2 and the PALB2 genes (i.e. one pathogenic variant in each copy of the gene) are associated with an extremely rare autosomal recessive syndrome called Fanconi anemia. This condition is characterized by an increased risk for malignancy in children, including leukemia and certain solid tumors, bone marrow failure, and distinctive clinical features including radial abnormalities. Individuals found to carry a pathogenic variant in BRCA2 or PALB2 who are considering pregnancy should be offered reproductive counseling. Information Sheet on Breast Cancer High Risk Panel and PALB2 Page 2 of 5 GeneDx Revision Date: 07/2016

3 Reason for referral: 1) Identify the genetic basis of breast cancer for individuals who have features and/or a family history consistent with one of the hereditary cancer syndromes described above. 2) To possibly help determine appropriate clinical management recommendations based on a molecular diagnosis. 3) Identify family members at risk to develop features associated with a specific hereditary cancer syndrome. Methods: Genomic DNA from the submitted specimen was enriched for the complete coding region and splice site junctions of the genes on the panel using a proprietary targeted capture system developed by GeneDx. For PTEN, nucleotides c. 700 through c in the promoter region are also sequenced. The products were sequenced on either an Illumina MiSeq or HiSeq instrument with 2x150 or 2x100 paired end reads, respectively. The sequence was aligned to reference sequences based on human genome build GRCh37/UCSC hg19. Capillary sequencing was used to confirm all variants with clinical or uncertain significance and to analyze regions with inadequate coverage by Next Generation sequencing. If present, apparently homozygous variants were confirmed using alternate primer pairs to significantly reduce the possibility of allele drop out. Concurrent deletion/duplication testing was performed for all of the genes on the panel using either exon level array CGH or MLPA. Confirmation of copy number changes was performed by MLPA, qpcr, or repeat acgh analysis. Data analysis was performed using gene specific filtering. The array was designed to detect most single exon deletions and duplications. All sequence alterations are described according to the Human Genome Variation Society (HGVS) nomenclature guidelines. Benign and likely benign variants, if present, are not reported but are available upon request. The genes evaluated by this test are listed on the first page of the report. Test Performance: DNA sequencing will detect nucleotide substitutions and small insertions and deletions, while array CGH will detect exon level deletions and duplications. These methods are expected to be greater than 99% sensitive in detecting variants identifiable by sequencing or array CGH. The likelihood of a false positive result is expected to be <1%. Technical Limitations: Neither sequencing nor exon level acgh can reliably detect mosaicism, and cannot detect chromosomal aberrations. Deletions involving more than 20bp and insertions involving more than 10bp are not reliably detected by the sequencing methodology, and deletions or duplications of less than 250bp are not reliably detected by array CGH. Regions of certain genes have inherent sequence properties that yield suboptimal data, potentially impairing accuracy of the results. In the absence of mrna/cdna studies, we cannot completely exclude the possibility of undetectable clinically significant variants in certain regions of these genes. False negatives may also occur in the setting of bone marrow transplantation, recent blood transfusion, or suboptimal DNA quality. In individuals with active leukemia or lymphoma or with known chronic myeloid or lymphoid neoplasms (such as low grade MDS, CML, ET, P. vera, PMF, CLL), there is a possibility that testing of specimens containing leukocytes may detect an acquired somatic variant, resulting in a false positive result. In this situation, please contact one of our genetic counselors to discuss the utility of submitting an alternate specimen. Additionally, rare false negatives may occur when testing for a specific variant identified at a laboratory other than GeneDx if a positive control is not provided. Based on the specific array design and technology used, the reported coordinates of duplications and deletions at the exon or gene level can slightly differ among family members tested but, in general, relatives are expected to have the same copy number variant. The ability to detect genetic variants and naming conventions can differ among laboratories. Reporting of Results: Results will be interpreted and reported following recommendations of the American College of Medical Genetics as a guideline ( Variations detected by sequencing or deletion/duplication analysis will be analyzed and classified into the following categories based on current scientific knowledge. Our analysis includes a comprehensive assessment of the variation on a molecular and clinical level in order to determine its clinical significance and Information Sheet on Breast Cancer High Risk Panel and PALB2 Page 3 of 5 GeneDx Revision Date: 07/2016

4 classification. Trained PhD analysts perform a detailed review of the variation on the molecular level, including exhaustive searches of gene and locus specific databases and the Human Gene Mutation Database (HGMD), and genetic counselors and clinical molecular geneticists carefully review literature reports. Pathogenic Variant Examples of variations that may be reported as pathogenic include frameshift variants and nonsense variants that are predicted to result in premature protein truncation or mrna decay, canonical splice site variants, and previously reported missense variants that are recognized as disease causing. Likely Pathogenic Variant Variations for which there is significant, but not conclusive, evidence supporting pathogenicity will be classified as Likely Pathogenic. Variant of Uncertain Significance Variations for which there is not sufficient evidence for classification will be classified as Variant of Uncertain Significance. Negative No variation of clinical or uncertain significance was detected. Any variation detected and classified as a likely benign or benign variant based on population data, review of the literature, Human Gene Mutation Database (HGMD), and appropriate locus specific databases will not be reported. Specimen Requirements and Shipping/Handling: Blood: Two EDTA (lavender top) tubes containing 4 ml each whole sterile blood Oral Rinse: Saliva collected in at least 30mL of mouthwash using our GeneDx collection kit Extracted DNA: >20 µg Buccal Swab: For family member testing only (excluding deletion/duplication family testing) Test Codes and Turnaround Times Please contact us for price information: Test Code Description Turnaround Time J005 Breast Cancer High Risk Panel and PALB2 2 weeks References 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 May;72(5): (PMID ) Antoniou A et al. Breast cancer risk in families with mutations in PALB2. N Engl J Med Aug 7;371(6): (PMID ) Biron Shental T et al. High incidence of BRCA1 2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma. Eur J Surg Oncol Dec;32(10): (PMID ) Brooks Wilson AR. Germline E cadherin mutations in hereditary diffuse gastric cancer: assessment of 42 new families and review of genetic screening criteria. J Med Genet Jul;41(7): (PMID ) Byrnes GB et al. Are the so called low penetrance breast cancer genes, ATM, BRIP1, PALB2, and CHEK2, high risk for women with strong family histories? Breast Cancer Res. 2008;10(3):208. (PMID ) Canto MI et al. International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer. Gut Mar;62(3): (PMID ) Casadei S et al. Contribution of inherited mutations in the BRCA2 interacting protein PALB2 to familial breast cancer. Cancer Res Mar 15;71(6): (PMID ) Chen S and Parmigiani G. Meta anlaysis of BRCA1 and BRCA2 penetrance. J Clin Oncol Apr;25(11): (PMID ) Chompret A et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer Jun;82(12): (PMID ) Claus EB et al. The genetic attributable risk of breast and ovarian cancer. Cancer Jun 1;77(11): (PMID: ) Easton DF. How many more breast cancer predisposition genes are there? Breast Can Res Aug;1(1): (PMID ) Errko H et al. A recurrent mutation in PALB2 in Finnish cancer families. Nature Mar 15;446(7133): (PMID ) 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 Mar;62(3): (PMID ) Gonzalez PD et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol Mar 10;27(8): (PMID ) Information Sheet on Breast Cancer High Risk Panel and PALB2 Page 4 of 5 GeneDx Revision Date: 07/2016

5 Guilford P. E cadherin germline mutations in familial gastric cancer. Nature Mar 26;392(6674): (PMID ) Graeser MK et al. Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. J Clin Oncol Dec 10;27(35): (PMID ) Hisada M et al. Multiple primary cancers in families with Li Fraumeni syndrome. J Natl Cancer Inst Apr 15;90(8): (PMID ) Hobert JA and Eng C. PTEN hamartoma tumor syndrome: An overview. Genet Med 2009:11(10): (PMID ) Jones S et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science Apr 10;324(5924):217. (PMID ) Kaurah P. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA Jun 6;297(21): (PMID ) King MC et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science Oct;302(5645): (PMID ) Leide A et al. Cancer Risks for Male Carriers of Germline Mutations in BRCA1 or BRCA2: A Review of the Literature. J Clin Oncol Feb 15;22(4): (PMID ) Levine DA et al. Fallopian Tube and Primary Peritoneal Carcinomas Associated With BRCA Mutations. J Clin Oncol Nov 15;21(22): (PMID ) NCCN Guidelines. Gastric Cancer. (URL: [February 2016 accessed]. NCCN Guidelines. Genetic/Familial High Risk Assessment: Breast and Ovarian. (URL: [February 2016 accessed]. Olivier M et al. Li Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res Oct 15;63(20): (PMID ) Pennington KP et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer Jan;119(2): (PMID ) Pharoah PD et al. Incidence of gastric cancer and breast cancer in CDH1 (E cadherin) mutation carriers from hereditary diffuse gastric cancer families. Gastroenterology Dec;121(6): (PMID ) Pharoah PD et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet May;31(1):33 6. (PMID ) Rahman N et al. PALB2, which encodes a BRCA2 interacting protein, is a breast cancer susceptibility gene. Nat Genet Feb;39(2): (PMID ) Risch HA et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin cohort study in Ontario. J Natl Cncer Inst Dec;98(23): (PMID ) Ruijs MWG et al. TP53 germline mutation testing in 180 families suspected of LieFraumeni syndrome: mutation detection rate and relative frequency of cancers in different familial phenotypes. J Med Genet Jun;47(6): (PMID ) Slater EP et al. PALB2 mutations in European familial pancreatic cancer families. Clin Genet Nov;78(5): (PMID ) Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. SEER Cancer Statistics Review, : Lifetime Risk Tables (URL: [February 2016 accessed]. Van der Groep P, van der Wall E, and van Diest PJ. Pathology of hereditary breast cancer. Cell Oncol (Dordrecht) Apr;34(2): (PMID: ) Gene Most commonly associated cancers Associated recessive syndrome Management Guidelines BRCA1 NM_ BRCA2 NM_ CDH1 NM_ PALB2 NM_ PTEN NM_ TP53 NM_ Breast, Ovarian, Pancreatic, Prostate, Endometrial serous carcinoma^ Breast, Ovarian, Pancreatic, Prostate, Endometrial serous carcinoma^ Gastric, Breast, Colon (signet ring)^ Fanconi anemia, CAPS #, NCCN Gastric Breast, Pancreatic (possibly high risk)^ Fanconi anemia, CAPS # Breast, Thyroid, Endometrial Breast, Sarcoma, Brain, Hematologic malignancies, Adrenocortical, among others* Key Red font denotes significantly increased cancer risk. We consider significantly increased risk to be a relative risk of 4 or higher in relation to the general population risk. This translates to the following lifetime cancer risks: 50% breast cancer, 20% colon cancer, 11% endometrial cancer, 8% melanoma, 7% renal cancer, 6% pancreatic cancer, 6% ovarian cancer, 5% thyroid cancer, 4% gastric or small bowel cancer. Blue font denotes moderately increased cancer risk. We consider moderately increased risk to be a relative risk between 2 and 4 in relation to the general population risk. This translates to the following lifetime cancer risks: 24 49% breast cancer, 32 60% prostate cancer, 5 11% endometrial cancer, 3 6% pancreatic cancer. ^ Gene specific risk for this cancer type is not well defined. * High overall risk of cancer: 75% lifetime risk for males to develop cancer, nearly 100% risk for females. # CAPS International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer (Canto 2013). Information Sheet on Breast Cancer High Risk Panel and PALB2 Page 5 of 5 GeneDx Revision Date: 07/2016