Grant Number:	5U24CA258118-03 Interpret this number
Primary Investigator:	Godley, Lucy
Organization:	University Of Chicago
Project Title:	Myeloid Malignancy Variant Curation Expert Panel
Fiscal Year:	2023

Germline predisposition to hematopoietic malignancies is more common than previously appreciated and is best understood currently for the myeloid malignancies. Variants in genes such as RUNX1, GATA2, ANKRD26, ETV6, CEBPA, and DDX41 are among those commonly identified in patients. Recognizing the emerging importance of germline predisposition to myeloid malignancies, the World Health Organization included this entity as a provisional diagnostic category in its newest leukemia classification scheme. The American Society of Hematology (ASH) and ClinGen partnered in 2017 to pilot a Myeloid Malignancy Variant Curation Expert Panel (MM-VCEP) knowing that the consistent functional annotation of gene variants is crucial to clinical management, especially considering that allogeneic hematopoietic stem cell transplantation (HSCT) using related donors is a mainstay of treatment for myeloid leukemias. Drs. Lucy A. Godley and David Wu have co-chaired the MM-VCEP, which first developed RUNX1 variant curation rules, resulting in two publications: one that outlines the rules in detail, and the other that provides a more clinical perspective on how the rules change variant interpretation. The MM-VCEP is now engaged in developing similar rules for GATA2 variants, and to facilitate this process, they are employing the Delphi method to come to consensus on a formal description of GATA2 deficiency syndrome. The MM-VCEP has also been innovative as the first VCEP to develop rules for germline copy number variants and for variants in a non-coding GATA2 enhancer. As a highly motivated and productive group, the MM-VCEP seeks three years of support beyond the ASH funding commitment so that they can continue to curate RUNX1 and GATA2 variants according to our established rules and to develop curation rules for variants in four additional genes that confer risk for myeloid malignancies: (1-2) ANKRD26 and ETV6: Individuals with deleterious variants in ANKRD26 and ETV6 have life-long thrombocytopenia, decreased platelet function, and risk of developing myeloid malignancies, like germline carriers of deleterious RUNX1 mutations, allowing the MM-VCEP to develop these curation rules in one year; (3) CEBPA: Myeloid leukemias with bi-allelic CEBPA mutations have a favorable prognosis, and in about 10% of these cases, one of the CEBPA mutations is a germline mutation, usually the 5’ end mutation. For this reason, germline genetic testing for CEBPA variants is recommended for those whose malignant cells have bi-allelic mutations. (4) DDX41: Germline DDX41 mutations are the most common mutation causing myeloid malignancies, accounting for about 1% of all cases of acute myeloid leukemias. To date, all truncating DDX41 mutations are found as germline alleles, and several alleles are common in particular populations. Thus, the MM-VCEP seeks to continue its important work in providing worldwide standards for consistent variant curation so that patients at risk of developing myeloid malignancies can receive optimal care, especially at the time of consideration of related donors for HSCT; elective surgeries and childbirth for those with platelet defects; as well as appropriate surveillance for cancer detection and organ function.





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