||7U24CA258118-04 Interpret this number
||Northwestern University At Chicago
||Myeloid Malignancy Variant Curation
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.
Revision of RUNX1 variant curation rules.
, Luo X.
, Shah M.
, Walker T.
, Mehta N.
, Wu D.
, Godley L.A.
Blood advances, 2022-08-23; 6(16), p. 4726-4730.
Germline variants drive myelodysplastic syndrome in young adults.
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Leukemia, 2021 Aug; 35(8), p. 2439-2444.