PURPOSE: The ability of a single technology, next-generation sequencing, to provide both sequence and copy number variant (CNV) results has driven the merger of clinical cytogenetics and molecular genetics. Consequently, the distinction between the definition of a sequence variant and a CNV is blurry. As the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines for interpretation of sequence variants address CNV classification only sparingly, this study focused on adapting ACMG/AMP criteria for single-gene CNV interpretation. METHODS: CNV-specific modifications of the 2015 ACMG/AMP criteria were developed and their utility was independently tested by three diagnostic laboratories. Each laboratory team interpreted the same 12 single-gene CNVs using three systems: (1) without ACMG/AMP guidance, (2) with ACMG/AMP criteria, and (3) with new modifications. A replication study of 12 different CNVs validated the modified criteria. RESULTS: The adapted criteria system presented here showed improved concordance and usability for single-gene CNVs compared with using the ACMG/AMP interpretation guidelines focused on sequence variants. CONCLUSION: These single-gene CNV criteria modifications could be used as a supplement to the ACMG/AMP guidelines for sequence variants, allowing for a streamlined workflow and a step toward a uniform classification system for both sequence and copy number alterations.
PURPOSE: The ability of a single technology, next-generation sequencing, to provide both sequence and copy number variant (CNV) results has driven the merger of clinical cytogenetics and molecular genetics. Consequently, the distinction between the definition of a sequence variant and a CNV is blurry. As the 2015 American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards and guidelines for interpretation of sequence variants address CNV classification only sparingly, this study focused on adapting ACMG/AMP criteria for single-gene CNV interpretation. METHODS: CNV-specific modifications of the 2015 ACMG/AMP criteria were developed and their utility was independently tested by three diagnostic laboratories. Each laboratory team interpreted the same 12 single-gene CNVs using three systems: (1) without ACMG/AMP guidance, (2) with ACMG/AMP criteria, and (3) with new modifications. A replication study of 12 different CNVs validated the modified criteria. RESULTS: The adapted criteria system presented here showed improved concordance and usability for single-gene CNVs compared with using the ACMG/AMP interpretation guidelines focused on sequence variants. CONCLUSION: These single-gene CNV criteria modifications could be used as a supplement to the ACMG/AMP guidelines for sequence variants, allowing for a streamlined workflow and a step toward a uniform classification system for both sequence and copy number alterations.
Authors: A H Beggs; E P Hoffman; J R Snyder; K Arahata; L Specht; F Shapiro; C Angelini; H Sugita; L M Kunkel Journal: Am J Hum Genet Date: 1991-07 Impact factor: 11.025
Authors: Andre E Minoche; Ben Lundie; Greg B Peters; Thomas Ohnesorg; Mark Pinese; David M Thomas; Andreas Zankl; Tony Roscioli; Nicole Schonrock; Sarah Kummerfeld; Leslie Burnett; Marcel E Dinger; Mark J Cowley Journal: Genome Med Date: 2021-02-25 Impact factor: 11.117
Authors: Saradadevi Thanikachalam; Elizabeth Hodapp; Ta C Chang; Dayna Morel Swols; Filiz B Cengiz; Shengru Guo; Mohammad F Zafeer; Serhat Seyhan; Guney Bademci; William K Scott; Alana Grajewski; Mustafa Tekin Journal: Genes (Basel) Date: 2020-03-26 Impact factor: 4.096
Authors: Nerina C van der Merwe; Jaco Oosthuizen; Magdalena Theron; George Chong; William D Foulkes Journal: BMC Cancer Date: 2020-05-06 Impact factor: 4.430