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Author Notes:

See publication for full list of authors.

Correspondence to David Wu, University of Washington, 825 Eastlake Ave E, G7800, Seattle, WA 98109; e-mail: dwu2@uw.edu; and Lucy A. Godley, The University of Chicago, 5841 S Maryland Ave, MC 2115, Chicago, IL 60637; e-mail: lgodley@medicine.bsd.uchicago.edu

All of the authors participated in the construction and pilot testing of the RUNX1 curation rules and edited the manuscript; and X.L., S.F., S.M., D.W., and L.A.G. participated in the majority of the manuscript writing.

The VCEP thanks the ClinGen SVI Working Group as well as the Executive Committee of the Hereditary Cancer Clinical Domain Working Group.

Conflict-of-interest disclosures: S.E.P. is a member of the scientific advisory panel of Baylor Genetics Laboratories.

L.A.G. is a member of the scientific advisory board for Invitae, Inc., and receives royalties from UpToDate, Inc.

L.Z. received honoraria from Future Technology Research, LLC, Roche Diagnostics Asia Pacific, BGI, and Illumina.

A family member of L.Z. has a leadership position and ownership interest in the Shanghai Genome Center.

The remaining authors declare no competing financial interests.

Subjects:

Research Funding:

The NIH, National Human Genome Research Institute supported this work through U41HG009649 (X.L. and S.E.P.) and U41HG009650 (S.M. and J.E.R.); and the 2018 NIH/National Cancer Institute Leukemia SPORE DRP award (P50CA100632-16, project 00007529) (C.D.D).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Hematology
  • FAMILIAL PLATELET DISORDER
  • CHRONIC MYELOMONOCYTIC LEUKEMIA
  • ACUTE MYELOGENOUS LEUKEMIA
  • INHERITED THROMBOCYTOPENIA
  • INTERPRETATION GUIDELINES
  • CLINICAL LABORATORIES
  • TRANSCRIPTION FACTOR
  • SEQUENCE VARIANTS
  • POINT MUTATIONS
  • GENE

ClinGen Myeloid Malignancy Variant Curation Expert Panel recommendations for germline RUNX1 variants

Tools:

Journal Title:

Blood Advances

Volume:

Volume 3, Number 20

Publisher:

, Pages 2962-2979

Type of Work:

Article | Final Publisher PDF

Abstract:

Standardized variant curation is essential for clinical care recommendations for patients with inherited disorders. Clinical Genome Resource (ClinGen) variant curation expert panels are developing disease-associated gene specifications using the 2015 American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) guidelines to reduce curation discrepancies. The ClinGen Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) was created collaboratively between the American Society of Hematology and ClinGen to perform gene- and disease-specific modifications for inherited myeloid malignancies. The MM-VCEP began optimizing ACMG/AMP rules for RUNX1 because many germline variants have been described in patients with familial platelet disorder with a predisposition to acute myeloid leukemia, characterized by thrombocytopenia, platelet functional/ultrastructural defects, and a predisposition to hematologic malignancies. The 28 ACMG/AMP codes were tailored for RUNX1 variants by modifying gene/disease specifications, incorporating strength adjustments of existing rules, or both. Key specifications included calculation of minor allele frequency thresholds, formulating a semi-quantitative approach to counting multiple independent variant occurrences, identifying functional domains and mutational hotspots, establishing functional assay thresholds, and characterizing phenotype-specific guidelines. Preliminary rules were tested by using a pilot set of 52 variants; among these, 50 were previously classified as benign/likely benign, pathogenic/likely pathogenic, variant of unknown significance (VUS), or conflicting interpretations (CONF) in ClinVar. The application of RUNX1-specific criteria resulted in a reduction in CONF and VUS variants by 33%, emphasizing the benefit of gene-specific criteria and sharing internal laboratory data.

Copyright information:

© 2019 by The American Society of Hematology

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