120. Expert curation of FLT3 variants by the ClinGen FLT3 Somatic Cancer Variant Curation expert panel

Abstract

FMS-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase with key roles in the survival, proliferation, and differentiation of hematopoietic cells. FLT3 variants are the most common alterations in acute myeloid leukemia (AML), occurring in approximately 30% of all AML cases. Routine screening for FLT3 variants in AML patients is recommended by the World Health Organization and European LeukemiaNet guidelines, as early detection of FLT3 variants guides therapy using FDA-approved FLT3 inhibitors to achieve better outcomes. However, there is a lack of consistency in the curation, interpretation, and reporting of FLT3 sequence variants among molecular pathologists in the clinical diagnostic setting. To address these issues, the ClinGen Somatic Cancer Clinical Domain Working Group (CDWG) formed the FLT3 Somatic Cancer Variant Curation Expert Panel (SC-VCEP), which is composed of 24 multi-disciplinary experts including oncologists, hematopathologists, molecular pathologists, clinical lab directors, and biocurators with expertise in hematological malignancies. Our FLT3 SC-VCEP received step 1 approval from the ClinGen CDWG Oversight Committee in December 2021. This SC-VCEP is working to establish a consensus on interpreting FLT3 variants according to the AMP/ASCO/CAP and ClinGen/CGC/VICC guidelines (PMIDs: 27993330, 35101336). The FLT3 SC-VCEP will utilize the expertise of clinical laboratory practice standards for evaluating variants and will curate these interpretations in the Clinical Interpretations of Variants in Cancer (CIViC) platform with an aim to apply the newly created and approved rules to generate expert-panel approved FLT3 variant submissions. Upon consensus classification, these interpretations will also be publicly available through ClinVar.