Limited Availability of Variant-Specific Germline Data Creates Challenges in the Interpretation of Myeloid NGS Panels Open Access

• ANKRD26 VUSs complicate risk assessment in hematologic malignancy and may extend beyond the known pathogenic hotspot.

• Unexpected germline findings from NGS highlight the need for clearer guidance in interpreting and managing VUSs.

ANKRD26-related thrombocytopenia (ANKRD26-RT) is a rare inherited platelet disorder (IPD) that carries an increased predisposition to hematologic malignancy. We report the case of an unprovoked thrombus in an anemic patient who was discovered to have an ANKRD26 germline variant of uncertain significance (VUS), along with a 20q chromosomal deletion. This patient’s variant lies downstream of the recognized mutational hotspot known to be associated with thrombocytopenia and myeloid neoplasms, and, as a VUS, is not definitively diagnostic of ANKRD26-RT. In our 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). While three known cases of thrombosis have occurred in patients with ANKRD26-RT, there is no known association with hypercoagulability. The role of the ANKRD26 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 germline findings, and underlines the importance of contributing to genetic variant databases to optimize variant calling and recommendations for patients.