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. 2020 Feb;22(2):336-344.
doi: 10.1038/s41436-019-0655-2. Epub 2019 Sep 19.

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

Tracy Brandt  1 , Laura M Sack  2 , Dolores Arjona  2 , Duanjun Tan  2 , Hui Mei  2 , Hong Cui  2 , Hua Gao  2 , Lora J H Bean  3   4 , Arunkanth Ankala  3   4 , Daniela Del Gaudio  5 , Amy Knight Johnson  5 , Lisa M Vincent  2   6 , Caitlin Reavey  2 , Amy Lai  2 , Gabriele Richard  2 , Jeanne M Meck  2
Affiliations
Free article

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

Tracy Brandt et al. Genet Med. 2020 Feb.
Free article

Erratum in

Abstract

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.

Keywords: ACMG/AMP criteria; PVS1; copy number variant (CNV); variant classification guidelines; variant interpretation.

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