Using the ACMG/AMP framework to capture evidence related to predicted and observed impact on splicing: Recommendations from the ClinGen SVI Splicing Subgroup.

Autor:	Walker LC; Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand., Hoya M; Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain., Wiggins GAR; Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand., Lindy A; GeneDx, Gaithersburg, MD, USA., Vincent LM; Natera, Austin, TX, USA., Parsons MT; Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Canson DM; Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., Bis-Brewer D; GeneDx, Gaithersburg, MD, USA., Cass A; Ambry Genetics, Aliso Viejo, CA, USA., Tchourbanov A; Ambry Genetics, Aliso Viejo, CA, USA., Zimmermann H; Ambry Genetics, Aliso Viejo, CA, USA., Byrne AB; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Pesaran T; Ambry Genetics, Aliso Viejo, CA, USA., Karam R; Ambry Genetics, Aliso Viejo, CA, USA., Harrison SM; Ambry Genetics, Aliso Viejo, CA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. Electronic address: sharriso@broadinstitute.org., Spurdle AB; Population Health Program, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia; Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.
Jazyk:	angličtina
Zdroj:	American journal of human genetics [Am J Hum Genet] 2023 Jul 06; Vol. 110 (7), pp. 1046-1067. Date of Electronic Publication: 2023 Jun 22.
DOI:	10.1016/j.ajhg.2023.06.002
Abstrakt:	The American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) framework for classifying variants uses six evidence categories related to the splicing potential of variants: PVS1, PS3, PP3, BS3, BP4, and BP7. However, the lack of guidance on how to apply such codes has contributed to variation in the specifications developed by different Clinical Genome Resource (ClinGen) Variant Curation Expert Panels. The ClinGen Sequence Variant Interpretation Splicing Subgroup was established to refine recommendations for applying ACMG/AMP codes relating to splicing data and computational predictions. We utilized empirically derived splicing evidence to (1) determine the evidence weighting of splicing-related data and appropriate criteria code selection for general use, (2) outline a process for integrating splicing-related considerations when developing a gene-specific PVS1 decision tree, and (3) exemplify methodology to calibrate splice prediction tools. We propose repurposing the PVS1_Strength code to capture splicing assay data that provide experimental evidence for variants resulting in RNA transcript(s) with loss of function. Conversely, BP7 may be used to capture RNA results demonstrating no splicing impact for intronic and synonymous variants. We propose that the PS3/BS3 codes are applied only for well-established assays that measure functional impact not directly captured by RNA-splicing assays. We recommend the application of PS1 based on similarity of predicted RNA-splicing effects for a variant under assessment in comparison with a known pathogenic variant. The recommendations and approaches for consideration and evaluation of RNA-assay evidence described aim to help standardize variant pathogenicity classification processes when interpreting splicing-based evidence. Competing Interests: Declaration of interests A.L., L.M.V., S.H., H.Z., R.K., D.B.-B., A.C., A.T., and T.P. are employed by fee-for-service laboratories performing clinical sequencing services. (Copyright © 2023 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu