Article| Volume 24, ISSUE 4, P931-954, April 2022

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

  • Simone Feurstein
    Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL

    Section of Hematology, Oncology and Rheumatology, Department of Internal Medicine, Heidelberg University Hospital, Heidelberg, Germany
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  • Christopher N. Hahn
    Molecular Pathology Research Laboratory, Centre for Cancer Biology, SA Pathology and University of South Australia, Adelaide, South Australia, Australia

    Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
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  • Nikita Mehta
    Diagnostic Molecular Genetics Laboratory, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
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  • Lucy A. Godley
    Correspondence and requests for materials should be addressed to Lucy A. Godley, Section of Hematology/Oncology, Department of Medicine, 5841 S. Maryland Ave, MC 2115, Chicago, IL 60637
    Section of Hematology/Oncology, Department of Medicine, The University of Chicago, Chicago, IL

    Department of Human Genetics, The University of Chicago, Chicago, IL
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Published:February 17, 2022DOI:



      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.


      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.


      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.


      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.


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