Low Rate of Germline Investigation for Variants of Suspected Germline Origin Detected During the Diagnostic Work-Up of Myeloid Neoplasms.

Background: Genomic profiling of patients with myeloid neoplasms (MN) may detect variants with high variant allele frequency (VAF), indicating potential germline origin. All current guidelines recommend further investigation of such variants. Objective: To define the proportion of variants with suspected germline origin that prompted germline investigation in patients evaluated for MN in the clinical setting. Methods: We included 738 patients investigated for MN in Mid-Sweden between May 2020 and January 2023 with available sequencing data in genes of interest (GOI) according to the Nordic and other international guidelines. Results: In total, 90 patients (12%) carried pathogenic/likely pathogenic (P/LP) variants in GOI according to the Nordic guidelines, with TP53, RUNX1, and NRAS being the most common (n = 37, n = 27, and n = 9, respectively). The potential germline origin was investigated in 16/90 (18%) patients. Two patients (2/16, 12.5%) with germline variants were identified (DDX41 and RUNX1, n = 1, respectively). In patients treated with allogeneic stem-cells transplantation (n = 15) the investigation rate was higher (7/15, 47%, p < 0.005) compared to the non-transplanted ones. Applying the European Leukemia Net (ELN) guidelines the number of patients with variants in GOI increased up to 177 mainly due to the inclusion of TET2, while application of other international guidelines leads to similar results with the Nordic ones. Conclusion: We report a low investigation rate for variants of suspected germline origin detected during the genomic profiling of patients investigated for MN in the clinical setting. Our study underscores the need for further awareness regarding germline investigation for hematological malignancies. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.