Splenic hamartoma in two related patients with BAP1 tumour predisposition syndrome caused by a novel germline BAP1 p.(Gly128Arg) missense variant

BAP1 tumour predisposition syndrome ( BAP1 -TPDS) is a hereditary cancer syndrome caused by heterozygous pathogenic germline variants in BAP1 . BAP1 -TPDS is associated with an increased risk for various malignant tumours, the core of which is uveal and cutaneous melanoma, malignant mesothelioma, and renal cell carcinoma. In BAP1 -TPDS, the majority of disease-causing BAP1 variants are null variants, although missense variants have been reported. We report a patient with BAP1 -TPDS caused by the novel germline BAP1 missense variant NM_004656.4:c.382G > A, p.(Gly128Arg). The patient developed BAP1 -inactivated melanocytic tumours, clear-cell renal cell carcinoma, and splenic hamartoma. An incidental splenic hamartoma was detected in existing tissue slides from the patient’s deceased first-degree relative, who was an obligate carrier for BAP1 -TPDS. In both splenic hamartomas, loss of BAP1 nuclear staining was detected in a subset of cells on immunohistochemistry. To our knowledge, this is the first report with immunohistochemical data supporting biallelic loss of BAP1 as a contributing step in the development of a splenic hamartoma in a patient with BAP1 -TPDS. It supports expanding the tumour spectrum of BAP1 -TPDS to splenic hamartoma and possibly other benign splenic tumours.