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

## TL;DR

A new BAP1 gene variant causes a rare tumor condition in two related patients, including a previously unreported type of benign spleen tumor.

## Contribution

First report of splenic hamartoma in BAP1 tumour predisposition syndrome with immunohistochemical evidence of biallelic BAP1 loss.

## Key findings

- A novel BAP1 germline missense variant p.(Gly128Arg) was identified in a patient with BAP1-TPDS.
- Splenic hamartoma was found in two related patients with BAP1-TPDS, with loss of BAP1 staining in tumor cells.
- This expands the known tumor spectrum of BAP1-TPDS to include splenic hamartoma.

## Abstract

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.

The online version contains supplementary material available at 10.1007/s10689-026-00538-3.