130. The Myeloid Malignancy Variant Curation Expert Panel: Investigating RUNX1, GATA2, and DDX41

Abstract

The Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP; https://clinicalgenome.org/affiliation/50034/) was established by the American Society of Hematology and ClinGen and is supported since 2021 by the National Cancer Institute to provide curation rules for genes in which variants confer risk to myeloid malignancies. The MM-VCEP is currently focused on developing and refining curation rules for RUNX1, GATA2, and DDX41. In 2019, the MM-VCEP published specifications for RUNX1 variant curation, which were updated in 2021 and are pending publication. Informed by these its version 2 updates, the MM-VCEP actively curates RUNX1 variants deposited into ClinVar. The group is also initiating the specification of variant curation rules for DDX41, the gene most commonly driving inherited adult-onset myeloid malignancies. To create rule specifications for GATA2 variant curation, the MM-VCEP has embarked on a project to define the GATA2 deficiency phenotype utilizing data from multiple centers. The MM-VCEP is employing a modified Delphi method to define a consensus-based phenotypic description of GATA2 deficiency. The MM-VCEP has assembled, and is now analyzing, patient-level genotype and phenotype data from 446 individuals, 339 with confirmed germline GATA2 mutations and 107 with suspected germline variants, from 17 centers in 7 countries globally, representing the largest compilation of GATA2 deficiency data to date, and the only one to assemble data from multiple centers. We aim to soon develop an evidence-based definition of the GATA2-deficient phenotype. Ultimately, through our concerted efforts, the MM-VCEP aims to facilitate consistent gene variant curation globally, to advance a deeper understanding of myeloid malignancies.