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Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants

2019; Elsevier BV; Volume: 22; Issue: 2 Linguagem: Inglês

10.1038/s41436-019-0655-2

1530-0366

Tracy Brandt, Laura M. Sack, Dolores Arjona, Duanjun Tan, Hui Mei, Hong Cui, Hua Gao, Lora Jh Bean, Arunkanth Ankala, Daniela del Gaudio, Amy Knight Johnson, Lisa M. Vincent, Caitlin Reavey, Amy Lai, Gabriele Richard, Jeanne Meck,

BRCA gene mutations in cancer

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.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.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.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.