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GeneDx
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 888-729-1206
Fax: 301-710-6594
E-mail: [email protected]
www.genedx.com/oncology
Test Information Sheet
OncoGeneDx: Breast Cancer High Risk Panel Gene List for the OncoGeneDx Breast Cancer High Risk Panel: BRCA1 BRCA2 CDH1 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 includes genes associated with well‐described hereditary cancer predisposition syndromes, including hereditary breast and ovarian cancer syndrome (BRCA1 and BRCA2), hereditary diffuse gastric cancer syndrome (CDH1), PTEN hamartoma tumor syndrome (PTEN) and Li‐Fraumeni syndrome (TP53). 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 and TP53 genes to familial breast cancer risk overall is less well‐characterized but is considerably lower than the contribution of pathogenic BRCA1 and BRCA2 variants. Hereditary Breast and Ovarian Cancer syndrome (BRCA1 and BRCA2): Women with pathogenic BRCA1 or BRCA2 variants 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 pathogenic BRCA1 variant carriers and 11‐27% for pathogenic BRCA2 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 males with a pathogenic BRCA2 variant is approximately 7%,and slightly increased with a pathogenic BRCA1 variant (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 CDH1 variant 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 pathogenic CDH1 variant carriers, 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 pathogenic CDH1 variants (Brooks‐Wilson 2004). 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). Information Sheet on Breast Cancer High Risk Panel Page 1 of 5 © GeneDx Revision Date: 07/2016 Additional clinical features in CS include increased head circumference ≥97th 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 PTEN variants. 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 BRCA1, BRCA2, CDH1, PTEN and TP53 can be found in the NCCN Clinical Practice Guidelines in Oncology Genetic/Familial High‐Risk Assessment: Breast and Ovarian at www.nccn.org. 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) and Li‐Fraumeni syndrome (TP53) are inherited in an autosomal dominant manner. While de novo pathogenic variants in the BRCA1, BRCA2, and CDH1 genes are uncommon, de novo pathogenic variants in PTEN and TP53 have been shown to occur in a subset of cases. Biallelic pathogenic variants in the BRCA2 gene (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 BRCA2 variant who are considering pregnancy should be offered reproductive counseling. 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) 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. 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 Information Sheet on Breast Cancer High Risk Panel Page 2 of 5 © GeneDx Revision Date: 07/2016 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. For PTEN, nucleotides c.‐700 through c.‐1300 in the promoter region are also sequenced. 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 (www.acmg.net). 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 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, previously reported missense variants that are recognized as disease‐causing and gross rearrangements. 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. Information Sheet on Breast Cancer High Risk Panel Page 3 of 5 © GeneDx Revision Date: 07/2016 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 B521‐6 Breast Cancer High Risk Panel 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. 2003 May;72(5):1117‐30. (PMID 12677558) 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. 2006 Dec;32(10):1097‐
100. (PMID 16650962) 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. 2004 Jul;41(7):508‐17. (PMID 15235021) 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. 2013 Mar;62(3):339‐47. (PMID 23135763) Chen S and Parmigiani G. Meta‐anlaysis of BRCA1 and BRCA2 penetrance. J Clin Oncol. 2007 Apr;25(11):1329‐33. (PMID 17416853) Chompret A et al. P53 germline mutations in childhood cancers and cancer risk for carrier individuals. Br J Cancer. 2000 Jun;82(12):1932‐7. (PMID 10864200) Claus EB et al. The genetic attributable risk of breast and ovarian cancer. Cancer. 1996 Jun 1;77(11):2318‐24. (PMID: 8635102) Easton DF. How many more breast cancer predisposition genes are there? Breast Can Res. 1999 Aug;1(1):14‐17. (PMID 11250676) 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 Mar;62(3):676‐89. (PMID 9497246) Gonzalez PD et al. Beyond Li Fraumeni Syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol. 2009 Mar 10;27(8):1250‐6. (PMID 19204208) Guilford P. E‐cadherin germline mutations in familial gastric cancer. Nature. 1998 Mar 26;392(6674):402‐5. (PMID 9537325) Graeser MK et al. Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers. J Clin Oncol. 2009 Dec 10;27(35): 5887‐92. (PMID 19858402) Hisada M et al. Multiple primary cancers in families with Li‐Fraumeni syndrome. J Natl Cancer Inst. 1998 Apr 15;90(8):606‐11. (PMID 9554443) Hobert JA and Eng C. PTEN hamartoma tumor syndrome: An overview. Genet Med 2009:11(10):687– 694. (PMID 19668082) Kaurah P. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007 Jun 6;297(21):2360‐72. (PMID 17545690) King MC et al. Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science. 2003 Oct;302(5645):643‐6. (PMID 14576434) Leide A et al. Cancer Risks for Male Carriers of Germline Mutations in BRCA1 or BRCA2: A Review of the Literature. J Clin Oncol. 2004 Feb 15;22(4):735‐42. (PMID 14966099) Levine DA et al. Fallopian Tube and Primary Peritoneal Carcinomas Associated With BRCA Mutations. J Clin Oncol. 2003 Nov 15;21(22):4222‐7. (PMID 14615451) NCCN Guidelines. Gastric Cancer. (URL: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp) [February 2016 accessed]. NCCN Guidelines. Genetic/Familial High‐Risk Assessment: Breast and Ovarian. (URL: http://www.nccn.org/professionals/physician_gls/f_guidelines.asp) [February 2016 accessed]. Olivier M et al. Li‐Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res. 2003 Oct 15;63(20):6643‐50. (PMID 14583457) Pennington KP et al. BRCA1, TP53, and CHEK2 germline mutations in uterine serous carcinoma. Cancer. 2013 Jan;119(2):332‐8. (PMID 22811390) 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 Dec;121(6):1348‐53. (PMID 11729114) Pharoah PD et al. Polygenic susceptibility to breast cancer and implications for prevention. Nat Genet. 2002 May;31(1):33‐6. (PMID 11984562) Risch HA et al. Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin‐cohort study in Ontario. J Natl Cncer Inst. 2006 Dec;98(23):1694‐706. (PMID 17148771) 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. 2010 Jun;47(6):421‐8. (PMID 20522432) Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute. SEER Cancer Statistics Review, 1975‐2012: Lifetime Risk Tables (URL: http://surveillance.cancer.gov/devcan) [February 2016 accessed]. Van der Groep P, van der Wall E, and van Diest PJ. Pathology of hereditary breast cancer. Cell Oncol (Dordrecht). 2011 Apr;34(2):71‐88. (PMID: 21336636) Information Sheet on Breast Cancer High Risk Panel Page 4 of 5 © GeneDx Revision Date: 07/2016 Gene Most commonly associated cancers BRCA1 Breast, Ovarian, Pancreatic, Prostate,
Endometrial serous carcinoma^ Breast, Ovarian, Pancreatic, Prostate, Endometrial serous carcinoma^ NM_007294.3 BRCA2 NM_000059.3 Associated recessive syndrome PTEN NM_000314.4 TP53 NM_000546.5 Gastric, Breast, Colon (signet ring)^ Breast, Thyroid, Endometrial Breast, Sarcoma, Brain, Hematologic malignancies, Adrenocortical, among others* NCCN‐BR/OV Fanconi anemia NCCN‐BR/OV, CAPS# NCCN‐BR/OV, NCCN‐Gastric CDH1 NM_004360.3 Management Guidelines NCCN‐BR/OV NCCN‐BR/OV 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 Page 5 of 5 © GeneDx Revision Date: 07/2016