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Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants.
Genet Med. 2020 Feb; 22(2):336-344.GM

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.

Links

Publisher Full Text (DOI)

Authors+Show Affiliations

Brandt T
GeneDx, Gaithersburg, MD, USA. tbrandt@genedx.com.
Sack LM
GeneDx, Gaithersburg, MD, USA.
Arjona D
GeneDx, Gaithersburg, MD, USA.
Tan D
GeneDx, Gaithersburg, MD, USA.
Mei H
GeneDx, Gaithersburg, MD, USA.
Cui H
GeneDx, Gaithersburg, MD, USA.
Gao H
GeneDx, Gaithersburg, MD, USA.
Bean LJH
Department of Human Genetics, Emory University, Atlanta, GA, USA. EGL Genetic Diagnostics LLC, Tucker, GA, USA.
Ankala A
Department of Human Genetics, Emory University, Atlanta, GA, USA. EGL Genetic Diagnostics LLC, Tucker, GA, USA.
Del Gaudio D
Department of Human Genetics, University of Chicago Genetic Services Laboratory, The University of Chicago, Chicago, IL, USA.
Knight Johnson A
Department of Human Genetics, University of Chicago Genetic Services Laboratory, The University of Chicago, Chicago, IL, USA.
Vincent LM
GeneDx, Gaithersburg, MD, USA. Children's National Health System, Washington, DC, USA.
Reavey C
GeneDx, Gaithersburg, MD, USA.
Lai A
GeneDx, Gaithersburg, MD, USA.
Richard G
GeneDx, Gaithersburg, MD, USA.
Meck JM
GeneDx, Gaithersburg, MD, USA.

MeSH

Computational BiologyDNA Copy Number VariationsGene DosageGenetic TestingGenetic VariationGenome, HumanGenomicsHigh-Throughput Nucleotide SequencingHumansLaboratoriesMutationSequence Analysis, DNA

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31534211

Citation

Brandt, Tracy, et al. "Adapting ACMG/AMP Sequence Variant Classification Guidelines for Single-gene Copy Number Variants." Genetics in Medicine : Official Journal of the American College of Medical Genetics, vol. 22, no. 2, 2020, pp. 336-344.
Brandt T, Sack LM, Arjona D, et al. Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants. Genet Med. 2020;22(2):336-344.
Brandt, T., Sack, L. M., Arjona, D., Tan, D., Mei, H., Cui, H., Gao, H., Bean, L. J. H., Ankala, A., Del Gaudio, D., Knight Johnson, A., Vincent, L. M., Reavey, C., Lai, A., Richard, G., & Meck, J. M. (2020). Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants. Genetics in Medicine : Official Journal of the American College of Medical Genetics, 22(2), 336-344. https://doi.org/10.1038/s41436-019-0655-2
Brandt T, et al. Adapting ACMG/AMP Sequence Variant Classification Guidelines for Single-gene Copy Number Variants. Genet Med. 2020;22(2):336-344. PubMed PMID: 31534211.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Adapting ACMG/AMP sequence variant classification guidelines for single-gene copy number variants. AU - Brandt,Tracy, AU - Sack,Laura M, AU - Arjona,Dolores, AU - Tan,Duanjun, AU - Mei,Hui, AU - Cui,Hong, AU - Gao,Hua, AU - Bean,Lora J H, AU - Ankala,Arunkanth, AU - Del Gaudio,Daniela, AU - Knight Johnson,Amy, AU - Vincent,Lisa M, AU - Reavey,Caitlin, AU - Lai,Amy, AU - Richard,Gabriele, AU - Meck,Jeanne M, Y1 - 2019/09/19/ PY - 2019/4/22/received PY - 2019/9/3/accepted PY - 2019/9/20/pubmed PY - 2021/1/12/medline PY - 2019/9/20/entrez KW - ACMG/AMP criteria KW - PVS1 KW - copy number variant (CNV) KW - variant classification guidelines KW - variant interpretation SP - 336 EP - 344 JF - Genetics in medicine : official journal of the American College of Medical Genetics JO - Genet Med VL - 22 IS - 2 N2 - 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. SN - 1530-0366 UR - https://www.unboundmedicine.com/medline/citation/31534211 DB - PRIME DP - Unbound Medicine ER -
Grapherence [↓90 ↑1]

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