A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias

• Verfasst von: Feurstein, Simone [VerfasserIn]
• Verfasst von: Hahn, Christopher N. [VerfasserIn]
• Verfasst von: Mehta, Nikita [VerfasserIn]
• Verfasst von: Godley, Lucy A. [VerfasserIn]
• Titel: A practical guide to interpreting germline variants that drive hematopoietic malignancies, bone marrow failure, and chronic cytopenias
• Verf.angabe: Simone Feurstein, Christopher N. Hahn, Nikita Mehta, Lucy A. Godley
• E-Jahr: 2022
• Jahr: 19 January 2022
• Umfang: 24 S.
• Fussnoten: Gesehen am 20.07.2022
• Titel Quelle: Enthalten in: Genetics in medicine
• Ort Quelle: Amsterdam : Elsevier, 1998
• Jahr Quelle: 2022
• Band/Heft Quelle: 24(2022), 4, Seite 931-954
• ISSN Quelle: 1530-0366
• DOI: doi:10.1016/j.gim.2021.12.008
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: ACMG/AMP criteria
• Sach-SW: Bone marrow failure
• Sach-SW: Cytopenia
• Sach-SW: Germline variant curation
• Sach-SW: Hematopoietic malignancies
• K10plus-PPN: 1811014216

Abstract

Purpose - The American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines for germline variant interpretation are implemented as a broad framework by standardizing variant interpretation. These rules were designed to be specified, but this process has not been performed for most of the 200 genes associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias. Because guidelines on how to perform these gene specifications are lacking, variant interpretation is less reliable and reproducible. - Methods - We have used a variety of methods such as calculations of minor allele frequencies, quasi-case-control studies to establish thresholds, proband counting, and plotting of receiver operating characteristic curves to compare different in silico prediction tools to design recommendations for variant interpretation. - Results - We herein provide practical recommendations for the creation of thresholds for minor allele frequencies, in silico predictions, counting of probands, identification of functional domains with minimal benign variation, use of constraint Z-scores and functional evidence, prediction of nonsense-mediated decay, and assessment of phenotype specificity. - Conclusion - These guidelines can be used by anyone interpreting variants associated with inherited hematopoietic malignancies, bone marrow failure, and cytopenias to develop criteria for reliable, accurate, and reproducible germline variant interpretation.