A practical guide to interpreting germline variants that drive hematopoietic malignancies,bone marrow failure,and chronic cytopenias |
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| Authors: | Simone Feurstein Christopher N Hahn Nikita Mehta Lucy A Godley |
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| Institution: | 1. Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL;2. Section of Hematology, Oncology and Rheumatology, Department of Internal Medicine, Heidelberg University Hospital, Heidelberg, Germany;3. Molecular Pathology Research Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia;4. Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia;5. Diagnostic Molecular Genetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY;6. Department of Human Genetics, The University of Chicago, Chicago, IL;1. Division of Human Genetics, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;2. MRC Unit for Genomic and Precision Medicine, Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;3. Department of Biochemistry and Medical Microbiology, School of Medicine, University of Namibia, Windhoek, Namibia;4. Division of Medical Virology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;5. Division of Human Genetics, Department of Pathology, Colorectal Cancer Research Group, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa;1. The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA;2. Department of Biostatistics, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;3. Department of Health Policy, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;4. Institute for Public Health Genetics, University of Washington School of Public Health, Seattle, WA;5. Department of Health Policy & Behavioral Sciences, School of Public Health, Georgia State University, Atlanta, GA;6. Genomic Medicine Institute, Geisinger, Danville, PA;7. Department of Population Health Sciences, Geisinger, Danville, PA;8. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN;1. Genomics Policy Unit, University of South Wales, Pontypridd, United Kingdom;2. William F. Connell School of Nursing, Boston College, Chestnut Hill, MA;3. Genetics Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;4. School of Nursing, University of Northern British Columbia, Prince George, British Columbia, Canada;5. Ross and Carol Nese College of Nursing, The Pennsylvania State University, University Park, PA;6. Genetic Counselling, Genomics England, London, United Kingdom;1. Faculty of Social Sciences, Business, and Economics, Åbo Akademi University, Turku, Finland;2. Institute of Biomedicine, Faculty of Medicine, University of Turku, Turku, Finland;3. Jyväskylä University School of Business and Economics, University of Jyväskylä, Jyväskylä, Finland;4. Labour Institute for Economic Research, Helsinki, Finland;5. IZA Institute of Labor Economics, Bonn, Germany;6. Department of Dermatology and Venereology, Department of Clinical Medicine, Faculty of Medicine, University of Turku, Turku, Finland;7. Department of Dermatology, Turku University Hospital, Turku, Finland;8. Department of Dermatology and Venereology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden;9. Department of Dermatology and Venereology, Region Västra Götaland, Sahlgrenska University Hospital, Gothenburg, Sweden;1. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA;2. Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;3. Department of Neuropediatrics, Jena University Hospital, Jena, Germany;4. Center for Rare Diseases, Jena University Hospital, Jena, Germany;1. Australian Genomics Health Alliance, Melbourne, Victoria, Australia;2. Genomics in Society, Murdoch Children''s Research Institute, Melbourne, Victoria, Australia;3. Department of Paediatrics, Melbourne Medical School, The University of Melbourne, Melbourne, Victoria, Australia |
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| Abstract: | PurposeThe American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for germline variant interpretation are implemented as a broad framework by standardizing variant interpretation. These rules were designed to be specified, but this process has not been performed for most of the 200 genes associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias. Because guidelines on how to perform these gene specifications are lacking, variant interpretation is less reliable and reproducible.MethodsWe have used a variety of methods such as calculations of minor allele frequencies, quasi-case–control studies to establish thresholds, proband counting, and plotting of receiver operating characteristic curves to compare different in silico prediction tools to design recommendations for variant interpretation.ResultsWe herein provide practical recommendations for the creation of thresholds for minor allele frequencies, in silico predictions, counting of probands, identification of functional domains with minimal benign variation, use of constraint Z-scores and functional evidence, prediction of nonsense-mediated decay, and assessment of phenotype specificity.ConclusionThese guidelines can be used by anyone interpreting variants associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias to develop criteria for reliable, accurate, and reproducible germline variant interpretation. |
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| Keywords: | ACMG/AMP criteria Bone marrow failure Cytopenia Germline variant curation Hematopoietic malignancies |
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