41. Step 2 updates for the oncogenic assessment of FLT3 variants by the ClinGen FLT3 somatic cancer variant curation expert

Variant interpretation guidelines aid genetic professionals in assessing the strength of evidence for the variant pathogenicity and clinical significance. Currently, there are no standard guidelines for evaluation of FLT3 variants, leading to variability in interpretation of FLT3 tyrosine kinase and non-tyrosine kinase variants. The FLT3 Somatic Cancer Variant Curation Expert Panel (SC-VCEP), within the ClinGen Somatic Cancer CDWG, is actively developing the variant oncogenicity interpretation rules for the FLT3 gene using ClinGen/CGC/VICC (PMID: 35101336) to facilitate accurate classification of FLT3 variants.

We will provide an update on the FLT3-specific modifications to evidence criteria OP1/SBP1 and OP4/SBS1. To address OP1/SBP1 we assessed multiple in silico prediction tools and their performance on FLT3-specific variants. Based on the analysis, we selected ClinPred and REVEL as optimal prediction tools for further evaluation during the pilot phase. We also modify the population allele frequency criteria for OP4/SBS1 using the spectrum of allele frequency of FLT3 variants. Recognizing the need for applicability to internal tandem duplication (ITD) variants, the strength of OM2 has been increased to OM2_strong for this variant type. With these updates, all rules have been evaluated and modifications/specifications proposed for OVS1, OS2/SBS2, OS3/OM3/OP3, OM1, OM2, OP1/SBP1, OP2, SBVS1, and OP4/SBS1. Once approved, the validity of the rules will be assessed on a set of pilot variants.