Clinical DNA Variant Interpretation

Conxi Lázaro PhD, is Head of the Molecular Diagnostic Laboratory, Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL-CIBERONC at Hospitalet de Llobregat, Barcelona, Spain. Dr Lazaro is a molecular geneticist with more than 25 years of experience in the field of human genetics. She did her PhD in Human Genetics at University of Barcelona. She has worked in several clinical hospitals in Barcelona. She was an invited professor at Massachusetts General Hospital Cancer Center at Boston in 2003/04 and did a sabbatical stay at Mount Sinai Hospital and at Women's College Hospital in Toronto in 2018/19. In the last ten years she has been involved in several projects aimed at using Next Generation Sequencing (NGS) for genetic testing purposes. Her field of expertise is Hereditary Cancer although she has worked on other genetic disorders. Of relevance was her pivotal research in the genetic basis of Neurofibromatosis type 1 (NF1) since the gene was discovered and her current work on the development of new therapeutic strategies for malignant tumors associated with NF1. She is member of several reputable international consortia and associations such as CIMBA, ENIGMA, CTF, GENTURIS and had been member of the Scientific Program Committee of the ESHG as well as treasurer of the Spanish association of human genetics (ASHG). Dr. Jordan Lerner-Ellis has 20 years of experience in molecular genetics and diagnostics. He is Director & Head of Advanced Molecular Diagnostics in the department of Pathology and Laboratory Medicine at Toronto’s Mount Sinai Hospital, Sinai Health System; Associate Professor at the University of Toronto, Laboratory Medicine & Pathobiology; and Clinician Scientist at the Lunenfeld-Tanenbaum Research Institute. His laboratory provides clinical diagnostic services for hereditary breast, ovarian and colon cancer, and other genetic testing areas, for Toronto and the province of Ontario. Dr Lerner-Ellis completed his PhD in human genetics at McGill University. He continued his studies at the Children’s Hospital in Basel, Switzerland before moving on to a postdoctoral fellowship in Molecular Biology at Harvard University, the Massachusetts General Hospital, and in Medical and Population Genetics at the Broad Institute. Following his postdoctoral studies, Dr. Lerner-Ellis completed the Clinical Molecular Genetics training program at Harvard Medical School, Brigham and Women’s Hospital and is certified as a diplomate of the American Board of Medical Genetics. Dr Lerner-Ellis’ core interest is in molecular diagnostics as currently applied to breast and colon cancer. His research is focused on improving genetic testing through greater reliance on new sequencing technologies. A concurrent aim of his research is to integrate genome sequencing into the general practice of medicine. Dr Lerner-Ellis is active in national and international data sharing, and variant interpretation efforts aimed at improving our understanding of the relationship between DNA variants and disease. Amanda Spurdle is an Associate Professor and Group Leader in Molecular Cancer Epidemiology at QIMR Berghofer Medical Research Institute, Australia. She co-founded and currently leads the ENIGMA international research consortium (http://www.enigmaconsortium.org/) aimed at improving and applying methods to determine the clinical significance of sequence variants in breast-ovarian cancer susceptibility genes. She is active in multiple expert panels dealing with interpretation of variants in cancer susceptibility genes. George P. Patrinos is a Professor of Pharmacogenomics and Pharmaceutical Biotechnology in the University of Patras (Greece), Department of Pharmacy, and Head of Division of Pharmacology and Biosciences of the same department and holds adjunct Full Professorships at Erasmus MC, Faculty of Medicine, and Health Sciences, Rotterdam (the Netherlands), and the United Arab Emirates University, College of Medicine, Department of Genetics and Genomics, Al-Ain (UAE). Also, from 2018 until the end of 2024, he was Chair of the Global Genomic Medicine Collaborative (G2MC). He served 12.5 years as a full member and Greece’s National representative in the CHMP Pharmacogenomics Working Party of the European Medicines Agency (EMA). George has more than 340 publications in peer-reviewed scientific journals, some of them in leading scientific journals, such as The Lancet, Nature Genetics, Nature Reviews Genetic, Nucleic Acids Research, Genes & Development. He has also coauthored and coedited more than 15 textbooks, among which the renowned textbook Molecular Diagnostics, published by Academic Press, now in its 3rd edition, while he is the editor of Translational and Applied Genomics book series, published by Elsevier. Furthermore, he serves as the Editor-In-Chief of the prestigious Pharmacogenomics Journal (TPJ), published by Nature Publishing Group, Associate Editor, and member of the editorial board of several scientific journals, and advisory and evaluation committees. Apart from that, George is the main coorganizer of the Golden Helix Conferences, an international meeting series on Pharmacogenomics and Genomic Medicine with more than 50 conferences organized in more than 25 countries worldwide.

• 1. Introduction: The challenge of genomic DNA interpretation Section I. Theoretical Chapters2. General considerations: Terminology and standards3. International consensus guidelines for constitutional sequence variant interpretation4. Quantitative modelling: Multifactorial integration of data 5. Clinical and genetic evidence and population evidence6. The computational approach to variant interpretation: principles, results, and applicability7. Functional evidence (I) transcripts and RNA splicing outline8. Functional evidence (II) protein and enzyme function 9. Somatic data usage for classification of germline variants 10. Pharmacogenomics and personalized medicine11. Data sharing and gene variant databases12. Approaches to the comprehensive interpretation of genome-scale sequencing13. Phenotype evaluation and clinical context: Application of case-level data in genomic variant interpretation Section II. Practical Chapters14. Inherited cardiomyopathies15. Phenylketonuria16. Hearing loss17. Familial hypercholesterolemia18. Classification of genetic variants in hereditary cancer genes19. RASopathies 20. Summary and conclusions