Limited availability of variant-specific germ line data creates challenges in the interpretation of myeloid NGS panels.

Abstract

<i>ANKRD26</i>-related thrombocytopenia (<i>ANKRD26</i>-RT) is a rare inherited platelet disorder that carries an increased predisposition to hematologic malignancy. We report the case of an unprovoked thrombus in a patient with anemia, who was discovered to have an <i>ANKRD26</i> germ line variant of uncertain significance (VUS), along with a 20q chromosomal deletion. This patient's variant lies downstream of the recognized mutational hot spot known to be associated with thrombocytopenia and myeloid neoplasms and, as a VUS, is not definitively diagnostic of <i>ANKRD26</i>-RT. In this case, the del(20q) supports the notion of somatic chromosomal abnormality in the context of unexplained anemia, suggestive of clonal cytopenia of undetermined significance (CCUS). Although 3 known cases of thrombosis have been reported in patients with <i>ANKRD26</i>-RT, there is no known association with hypercoagulability. The role of the <i>ANKRD26</i> VUS reported in this case vis-à-vis the patient's hypercoagulability and CCUS remains unclear. This case raises the question of whether hypercoagulability should be added to the expanding phenotypic spectrum of ANKRD26-related disorders, highlights the challenges of interpreting and managing unexpected germ line findings, and underlines the importance of contributing to genetic variant databases to optimize variant calling and recommendations for patients.