Peter Horak1, Malachi Griffith2, Arpad M Danos2, Beth A Pitel3, Subha Madhavan4, Xuelu Liu5, Cynthia Chow6, Heather Williams7, Leigh Carmody8, Lisa Barrow-Laing9, Damian Rieke10, Simon Kreutzfeldt11, Albrecht Stenzinger12, David Tamborero13, Manuela Benary10, Padma Sheila Rajagopal14, Cristiane M Ida3, Harry Lesmana15, Laveniya Satgunaseelan16, Jason D Merker17, Michael Y Tolstorukov5, Paulo Vidal Campregher18, Jeremy L Warner19, Shruti Rao4, Maya Natesan2, Haolin Shen2, Jeffrey Venstrom20, Somak Roy21, Kayoko Tao22, Rashmi Kanagal-Shamanna23, Xinjie Xu3, Deborah I Ritter24, Kym Pagel25, Kilannin Krysiak2, Adrian Dubuc26, Yassmine M Akkari27, Xuan Shirley Li28, Jennifer Lee29, Ian King30, Gordana Raca31, Alex H Wagner32, Marylin M Li33, Sharon E Plon24, Shashikant Kulkarni24, Obi L Griffith2, Debyani Chakravarty34, Dmitriy Sonkin35. 1. National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: peter.horak@nct-heidelberg.de. 2. Washington University School of Medicine in St. Louis, St. Louis, MO. 3. Mayo Clinic, Rochester, MN. 4. Georgetown University Medical Center, Washington, DC. 5. Dana-Farber Cancer Institute, Boston, MA. 6. BC Cancer Agency, Vancouver, British Columbia, Canada. 7. Columbia University, New York, NY. 8. The Jackson Laboratory for Genomic Medicine, Farmington, CT. 9. QIAGEN Inc, Redwood City, CA. 10. Charité-Universitätsmedizin Berlin, Berlin, Germany. 11. National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany. 12. Institute of Pathology, University of Heidelberg, Heidelberg, Germany. 13. Karolinska Institute, Stockholm, Sweden. 14. Cancer Data Science Laboratory, Center for Cancer Research, National Cancer Institute, Bethesda, MD. 15. Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH. 16. Royal Prince Alfred Hospital, Sydney, New South Wales, Australia. 17. UNC School of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC. 18. Hospital Israelita Albert Einstein, São Paulo, São Paulo, Brazil. 19. Vanderbilt University, Nashville, TN. 20. Foundation Medicine, Inc, Cambridge, MA. 21. Cincinnati Children's Hospital Medical Center, Cincinnati, OH. 22. National Cancer Center Hospital, Tokyo, Japan. 23. The University of Texas MD Anderson Cancer Center, Houston, TX. 24. Baylor College of Medicine, Houston, TX. 25. Johns Hopkins University, Baltimore, MD. 26. Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 27. Legacy Health, Portland, OR. 28. Congenica Ltd, Cambridge, United Kingdom. 29. Frederick National Laboratory for Cancer Research, National Cancer Institute, Rockville, MD. 30. University Health Network, Toronto, Ontario, Canada. 31. University of Southern California, Los Angeles, CA. 32. Nationwide Children's Hospital, Columbus, OH; The Ohio State University College of Medicine, Columbus, OH. 33. Children's Hospital of Philadelphia, Philadelphia, PA. 34. Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: chakravd@mskcc.org. 35. National Cancer Institute, Rockville, MD. Electronic address: dmitriy.sonkin@nih.gov.
Abstract
PURPOSE: Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. METHODS: Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS: This comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. CONCLUSION: The comprehensive SOP is now available for classification of oncogenicity of somatic variants.
PURPOSE: Several professional societies have published guidelines for the clinical interpretation of somatic variants, which specifically address diagnostic, prognostic, and therapeutic implications. Although these guidelines for the clinical interpretation of variants include data types that may be used to determine the oncogenicity of a variant (eg, population frequency, functional, and in silico data or somatic frequency), they do not provide a direct, systematic, and comprehensive set of standards and rules to classify the oncogenicity of a somatic variant. This insufficient guidance leads to inconsistent classification of rare somatic variants in cancer, generates variability in their clinical interpretation, and, importantly, affects patient care. Therefore, it is essential to address this unmet need. METHODS: Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group and ClinGen Germline/Somatic Variant Subcommittee, the Cancer Genomics Consortium, and the Variant Interpretation for Cancer Consortium used a consensus approach to develop a standard operating procedure (SOP) for the classification of oncogenicity of somatic variants. RESULTS: This comprehensive SOP has been developed to improve consistency in somatic variant classification and has been validated on 94 somatic variants in 10 common cancer-related genes. CONCLUSION: The comprehensive SOP is now available for classification of oncogenicity of somatic variants.
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