Leveraging paired germline and somatic analysis to improve the classification of <i>DDX41</i> variants

Constitutional pathogenic variants in DDX41 predispose to myelodysplasia and acute myeloid leukaemia. Acquisition of subsequent somatic hits in the second allele is frequent, with notable recurrent variants at key hotspots. Sequencing of Deoxyribonucleic acid from blood/marrow of 239 patients with suspected/confirmed haematological malignancies at a single centre within a 4-year period identified 136 unique DDX41 variants. Among those with co-occurring somatic and likely/confirmed germline variants, 54.8% of likely/confirmed germline variants were pathogenic when classified according to current Cancer Variant Interpretation Group UK (CanVIG-UK) guidelines (incorporating American College of Medical Genetics [ACMG] criteria), while 45.2% were deemed variants of uncertain significance (VUS). Classification of variants as uncertain poses challenges, as it then calls into question the underlying aetiology of the malignancy, as well as the significance of any subsequent somatic DDX41 variants. As carrier relatives of suspected deleterious DDX41 variants will not usually be considered as donors for bone marrow transplantation, classification of variants of likely germline origin will have immediate treatment implications. Current ACMG and CanVIG-UK guidelines do not permit co-occurrence with recurrent somatic driver variants as evidence favouring pathogenicity, despite this being a convincing finding. This study proposes modifying certain rules as a basis for developing DDX41-specific guidance, as it will significantly impact decisions surrounding bone marrow transplantation.