Cosegregation analysis following an excellent response to olaparib in a pancreatic cancer patient carrier of BRCA2:c.7892 T > C variant enables its reclassification from VUS to pathogenic

Abstract Identification of variants of uncertain significance (VUS) presents a great challenge in oncogenetics, especially in the era of personalised cancer treatment. We present a metastatic pancreatic cancer patient, referred for predictive genetic testing for treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, in whom a rare missense BRCA2:c.7892 T > C p.(Leu2631Pro), located in the DNA-binding domain, was identified. Extensive family history of cancers as well as data on other carriers, identified in our laboratory database of tested individuals, suggested hereditary breast and ovarian cancer (HBOC) syndrome. However, the variant could only be formally classified as a VUS at the time. In this exceptional case, an ad hoc board of experts was formed and proposed the patient be offered PARP inhibitors before time-consuming cosegregation analysis and formal reclassification of the VUS to pathogenic/likely pathogenic (P/LP) were completed. After a partial response to platinum-based chemotherapy, the patient consented to maintenance with olaparib and a 48-months long complete response was observed. Herein, we also present a formal reclassification of the variant BRCA2:c.7892 T > C from VUS to pathogenic after the completion of extensive cosegregation analysis in 71 members of a single large family originating from a specific northeastern region of Slovenia.