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Blueprint Genetics Comprehensive Hematology and Hereditary Cancer Comprehensive Hematology and Hereditary Cancer Panel Test code: HE1401 Is a 348 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of hematological disorder with genetic predisposition to malignancies. This panel is designed to detect heritable germline mutations and should not be used for the detection of somatic mutations in tumor tissue. Is not recommended for patients suspected to have anemia due to alpha-thalassemia (HBA1 or HBA2). These genes are highly homologous reducing mutation detection rate due to challenges in variant call and difficult to detect mutation profile (deletions and gene-fusions within the homologous genes tandem in the human genome). Is not recommended for patients with a suspicion of severe Hemophilia A if the common inversions are not excluded by previous testing. An intron 22 inversion of the F8 gene is identified in 43%-45% individuals with severe hemophilia A and intron 1 inversion in 2%-5% (GeneReviews NBK1404; PMID:8275087, 8490618, 29296726, 27292088, 22282501, 11756167). This test does not detect reliably these inversions. Is not recommended for patients suspected to have anemia due to alpha-thalassemia (HBA1 or HBA2). These genes are highly homologous reducing mutation detection rate due to challenges in variant call and difficult to detect mutation profile (deletions and gene-fusions within the homologous genes tandem in the human genome). About Comprehensive Hematology and Hereditary Cancer Inherited hematological diseases are a group of blood disorders with variable clinical presentation. Many of them predispose to malignancies and for example patients with inherited bone marrow failure syndromes (Fanconi anemia) have a high risk of developing cancer, either leukemia or solid tumors. Genetic testing is the most effective way to identify individuals with inherited hematological diseases and a genetic predisposition to develop malignancies. Accurate genetic diagnosis enables personal cancer risk assessment and inherited genetic variant can be taken into account when planning the treatment and the follow-up of both unaffected and affected persons. In most of the cases, cancer mortality can be significantly reduced in high- risk individuals by regular surveillance and preventive strategies. Gene Set Description Genes in the Comprehensive Hematology and Hereditary Cancer Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ABCA3 Interstitial lung disease, Surfactant metabolism dysfunction, AR 11 287 pulmonary ABCB7 Anemia, sideroblastic, and spinocerebellar ataxia XL 8 9 ABCG5 Sitosterolemia AR 13 42 ABCG8 Sitosterolemia AR 18 44 ACD Dyskeratosis congenita, autosomal dominant 6, Dyskeratosis AD/AR 2 8 congenita, autosomal recessive 7 ACTB* Baraitser-Winter syndrome AD 55 60 ACTN1 Bleeding disorder, platelet- AD 7 25 https://blueprintgenetics.com/ ADAMTS13 Schulman-Upshaw syndrome, Thrombotic thrombocytopenic purpura, AR 30 183 familial AIP Pituitary adenoma, familial isolated AD 53 110 AK1 Adenylate kinase deficiency, hemolytic anemia due to AR 8 10 AK2 Reticular dysgenesis AR 14 17 ALAS2 Anemia, sideroblastic, Protoporphyria, erythropoietic XL 27 103 ALK Neuroblastoma AD 31 15 AMN Megaloblastic anemia-1, Norwegian AR 29 34 ANK1 Spherocytosis AD/AR 20 105 ANKRD26 Thrombocytopenia AD 6 21 AP3B1 Hermansky-Pudlak syndrome AR 14 34 AP3D1 Hermansky-Pudlak syndrome 10 AR 1 4 APC Gardner syndrome, Desmoid disease, hereditary, Familial AD 773 1926 adenomatous polyposis ARPC1B Platelet abnormalities with eosinophilia and immune-mediated AR 2 4 inflammatory disease ATM Breast cancer, Ataxia-Telangiectasia AD/AR 1047 1109 ATR Cutaneous telangiectasia and cancer syndrome, Seckel syndrome AD/AR 10 33 ATRX Carpenter-Waziri syndrome, Alpha-thalassemia/mental retardation XL 65 165 syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith- Fineman-Myers syndrome, Mental retardation-hypotonic facies syndrome AXIN2 Oligodontia-colorectal cancer syndrome, Oligondontia, isolated AD 19 18 BAP1 Tumor predisposition syndrome AD 74 113 BARD1 Breast cancer AD 159 114 BLM Bloom syndrome AR 152 119 BLOC1S3 Hermansky-Pudlak syndrome AR 2 4 BLOC1S6 Hermansky-Pudlak syndrome AR 1 2 BMPR1A* Polyposis, juvenile intestinal AD 110 140 BRAF* LEOPARD syndrome, Noonan syndrome, Cardiofaciocutaneous AD 134 65 syndrome BRCA1* Pancreatic cancer, Breast-ovarian cancer, familial AD 2997 2631 BRCA2 Fanconi anemia, Medulloblastoma, Glioma susceptibility, Pancreatic AD/AR 3369 2659 cancer, Wilms tumor, Breast-ovarian cancer, familial BRIP1 Fanconi anemia, Breast cancer AD/AR 238 189 https://blueprintgenetics.com/ BUB1B Mosaic variegated aneuploidy syndrome, Premature chromatid AD/AR 14 28 separation trait C15ORF41 Congenital dyserythropoietic anemia AR 3 3 CBL Noonan syndrome-like disorder with or without juvenile AD 24 43 myelomonocytic leukemia CD70 Primary immunodeficiency AR 4 CDAN1 Anemia, dyserythropoietic congenital AR 12 61 CDC42 Takenouchi-Kosaki syndrome, Noonan-syndrome like phenotype AD 11 9 CDC73 Carcinoma, parathyroid, Hyperparathyroidism, Hyperparathyroidism- AD 50 101 jaw tumor syndrome CDH1 CDH1-related cancer, Blepharocheilodontic syndrome 1 AD 178 242 CDK4 Melanoma, cutaneous malignant AD 4 14 CDKN1B Multiple endocrine neoplasia AD 13 20 CDKN1C Beckwith-Wiedemann syndrome, IMAGE syndrome AD 35 81 CDKN2A Melanoma, familial, Melanoma-pancreatic cancer syndrome AD 87 232 CEBPA Acute myeloid leukemia, familial AD 15 13 CEP57 Mosaic variegated aneuploidy syndrome AR 5 5 CHEK2* Li-Fraumeni syndrome AD/AR 275 197 CLCN7 Osteopetrosis AD/AR 15 98 CLPB 3-methylglutaconic aciduria with cataracts, neurologic involvement, AR 26 25 and neutropenia (MEGCANN) CSF2RA* Surfactant metabolism dysfunction, pulmonary XL 2 17 CSF3R Neutrophilia, hereditary AD 13 13 CTC1 Cerebroretinal microangiopathy with calcifications and cysts AR 21 33 CTSC Periodontitis, juvenile, Haim-Munk syndrome, Papillon-Lefevre AR 19 92 syndrome CUBN* Megaloblastic anemia-1, Finnish AR 42 53 CXCR4 Warts, hypogammaglobulinemia, infections, and myelokathexis AD 5 15 (WHIM) syndrome CYB5R3 Methemoglobinemia due to methemoglobin reductase deficiency AR 21 71 CYCS* Thrombocytopenia AD 2 3 CYLD Spiegler-Brooke syndrome, Trichoepithelioma, multiple, AD 34 106 Cylindromatosis DDB2 Xeroderma pigmentosum AR 4 17 https://blueprintgenetics.com/ DDX41 Familial myeloproliferative/lymphoproliferative neoplasms, multiple AD 9 21 types, susceptibility to DHFR* Megaloblastic anemia due to dihydrofolate reductase deficiency AR 2 5 DICER1* DICER1 syndrome AD 197 137 DIS3L2* Perlman syndrome AR 12 14 DKC1 Hoyeraal-Hreidarsson syndrome, Dyskeratosis congenita XL 48 74 DNAJC21 Bone marrow failure syndrome 3 AR 5 11 DNASE2 Primary immunodeficiency 2 DTNBP1 Hermansky-Pudlak syndrome AR 2 3 EFL1 Shwachman-Diamond syndrome 3 2 EGFR Lung cancer, familial, susceptibilty to, Inflammatory skin and bowel AD/AR 55 18 disease, neonatal, Acute myeloid leukemia, familial EGLN1* Hemoglobin, high altitude adapation AD 3 64 ELANE Neutropenia AD 43 217 EPAS1 Erthyrocytosis, familial 4 AD 3 30 EPB41 Ellipsocytosis 1 AR 6 12 EPB42 Spherocytosis AR 8 17 EPCAM Diarrhea 5, with tufting enteropathy, congenital, Colorectal cancer, AD/AR 38 80 hereditary nonpolyposis EPOR Erythrocytosis, familial, 1 AD 4 32 ERCC1 Cerebrooculofacioskeletal syndrome 4 AR 8 5 ERCC2 Xeroderma pigmentosum, Trichothiodystrophy, photosensitive, AR 26 98 Cerebrooculofacioskeletal syndrome 2 ERCC3 Xeroderma pigmentosum, Trichothiodystrophy, photosensitive AR 10 19 ERCC4 Fanconi anemia, Xeroderma pigmentosum, XFE progeroid syndrome AR 13 70 ERCC5 Xeroderma pigmentosum, Xeroderma pigmentosum/Cockayne AR 21 54 syndrome ERCC6L2 Bone marrow failure syndrome 2 AR 4 9 ETV6 Thrombocytopenia 5 AD 10 38 EXO1 Lynch syndrome AD/AR 1 14 EXT1 Multiple cartilagenious exostoses 1 AD 97 523 EXT2 Multiple cartilagenious exostoses 2 AD 45 250 EZH2 Weaver syndrome AD 29 41 https://blueprintgenetics.com/ F10 Factor X deficiency AR 15 155 F11 Factor XI deficiency AD/AR 77 271 F12 Angioedema, Factor XII deficiency AD/AR 7 53 F13A1 Factor XIIIA deficiency AR 20 180 F13B Factor XIIIB deficiency AR 4 18 F2 Thrombophilia due to thrombin defect, Prothrombin deficiency, AD/AR 14 66 congenital F5 Factor V deficiency, Thrombophilia due to activated protein C AD/AR 19 157 resistance F7 Factor VII deficiency AR 27 322 F8* Hemophilia A XL 296 3205 F9 Hemophilia B, Warfarin sensitivity, Thrombophilia, due to factor IX XL 117 1281 defect FADD Infections, recurrent, with encephalopathy, hepatic dysfunction, and AR 2 1 cardiovascular malformations FAM111B Hereditary Fibrosing Poikiloderma with Tendon Contracture, AD 7 7 Myopathy, and Pulmonary Fibrosis, Lung cancer, familial, susceptibilty to FANCA Fanconi anemia AR 191 677 FANCB Fanconi anemia XL 11 21 FANCC Fanconi anemia AR 94 64 FANCD2* Fanconi anemia AR 21 61 FANCE Fanconi anemia AR 4 17 FANCF Fanconia anemia AR 7 16 FANCG Fanconi anemia AR 16 92 FANCI Fanconi anemia AR 13 45 FANCL Fanconi anemia AR 13 24 FANCM Fanconi anemia AR 6 50 FAS Autoimmune lymphoproliferative syndrome AD/AR 31 133 FASLG Autoimmune lymphoproliferative syndrome, type IB AD 2 10 FGA Afibrinogenemia, congenital, Dysfibrinogenemia, congenital, AD/AR 10 144 Hypodysfibrinogenemia, congenital, Familial visceral amyloidosis FGB Afibrinogenemia, congenital, Dysfibrinogenemia, congenital, AD/AR 6 92 Hypodysfibrinogenemia, congenital https://blueprintgenetics.com/ FGG Afibrinogenemia, congenital, Hypodysfibrinogenemia, AD/AR 7 127 Dysfibrinogenemia, congenital,
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