Melanoma of the eye is a rare and distinct subtype of melanoma, which only 
rarely are familial. However, cases of uveal melanoma (UM) have been found in 
families with mixed cancer syndromes. Here, we describe a comprehensive search 
for inherited genetic variation in a family with multiple cases of UM but no 
aggregation of other cancer diagnoses. The proband is a woman diagnosed with UM 
at 16 years who within 6 months developed liver metastases. We also identified 
two older paternal relatives of the proband who had died from UM. We performed 
exome sequencing of germline DNA from members of the affected family. Exome-wide 
analysis identified a novel loss-of-function mutation in the BAP1 gene, 
previously suggested as a tumor suppressor. The mutation segregated with the UM 
phenotype in this family, and we detected a loss of the wild-type allele in the 
UM tumor of the proband, strongly supporting a causative association with UM. 
Screening of BAP1 germline mutations in families predisposed for UM may be used 
to identify individuals at increased risk of disease. Such individuals may then 
be enrolled in preventive programs and regular screenings to facilitate early 
detection and thereby improve prognosis.