Page 28 - Haematologica April 2020

Ferrata Storti Foundation
Haematologica 2020 Volume 105(4):870-887
How I curate: applying American Society
of Hematology-Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel rules for RUNX1 variant curation for germline predisposition to myeloid malignancies
David Wu,1,* Xi Luo,2* Simone Feurstein,3 Chimene Kesserwan,4 Shruthi Mohan,5 Daniel E. Pineda-Alvarez,6 and Lucy A. Godley3,7 on behalf of the collaborative group of the American Society of Hematology - Clinical Genome Resource Myeloid Malignancy Variant Curation Expert Panel#
1Department of Laboratory Medicine, University of Washington, Seattle, WA;
2Department of Pediatrics/Hematology-Oncology, Baylor College of Medicine, Houston, TX; 3Section of Hematology/Oncology, Department of Medicine, and The University of Chicago Comprehensive Cancer Center, Chicago, IL; 4Albert Einstein College of Medicine, Department of Pathology, New York, NY; 5Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, NC; 6Invitae, San Francisco, CA and
7Department of Human Genetics, The University of Chicago, Chicago, IL, USA
*DW and XL contributed equally to this work.
#Members of this Clinical Genome Resource Variant Curation Expert Panel are listed in the Acknowledgments.
ABSTRACT
The broad use of next-generation sequencing and microarray plat- forms in research and clinical laboratories has led to an increasing appreciation of the role of germline mutations in genes involved in hematopoiesis and lineage differentiation that contribute to myeloid neo- plasms. Despite implementation of the American College of Medical Genetics and Genomics and Association for Molecular Pathology 2015 guidelines for sequence variant interpretation, the number of variants deposited in ClinVar, a genomic repository of genotype and phenotype data, and classified as having uncertain significance or being discordantly classified among clinical laboratories remains elevated and contributes to indeterminate or inconsistent patient care. In 2018, the American Society of Hematology and the Clinical Genome Resource co-sponsored the Myeloid Malignancy Variant Curation Expert Panel to develop rules for classifying gene variants associated with germline predisposition to myeloid neoplasia. Herein, we demonstrate application of our rules devel- oped for the RUNX1 gene to variants in six examples to show how we would classify them within the proposed framework.
Introduction
Germline mutations in genes involved in hematopoiesis and lineage differentia- tion predispose patients to myeloid neoplasia with or without thrombocytopenia. The broad adoption of next-generation sequencing and microarrays in the clinical laboratory has expanded our knowledge of germline contribution to myeloid neo- plasia. Drazer et al. reported that in six of 24 patients with myeloid neoplasia, pre- sumed somatic variants in DDX41, GATA2 and TP53 were of germline origin.1 Similarly, Churpek et al. showed that 29% of acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) kindreds with a positive family history carried a variant in one of 12 genes associated with germline predisposition to hematopoietic malignancies, including FANCA, GATA2, RUNX1, and SBDS.2 To date, more than 65 genes have been associated with a predisposition to hemato- logic malignancies.3 Recognizing the contribution of germline variation toward myeloid neoplasia, the ‘WHO classification of Tumors of Hematopoietic and
Correspondence:
DAVID WU
dwu2@uw.edu
LUCY A. GODLEY
lgodley@medicine.bsd.uchicago.edu
Received: July 16, 2019. Accepted: October 21, 2019. Pre-published: March 12, 2020
doi:10.3324/haematol.2018.214221
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/4/870
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