The challenge of ultra-rare, overlooked cancer predisposition syndromes <b>: unveiling the role of cancer genome profiling</b>

Abstract Cancer predisposition syndromes (CPSs) constitute an important branch of human genetics. Ultrarare CPSs are a growing and largely unexplored subset of such conditions. Uncertainties on the tumour risk spectrum can cause missed or delayed diagnoses and suboptimal care. In this review, we aim to shed light on the challenges that ultrarare CPSs can pose in recognition, cancer risk management, and clinical research. In addition, we explore the emerging role of cancer genomic profiling and mutational signature analysis, which holds promise in ultrarare CPSs for diagnosis, variant interpretation, and design of clinical management. Finally, we discuss future perspectives, highlighting the need for large-scale, collaborative efforts to collect and share genomic data, and emphasizing how the spread of cancer genome profiling will transform diagnostic reasoning and patient management by complementing – though not replacing – clinical judgement and phenotype characterization.