Of the 254 patients (median age [range], 56 [13-79] years; 179 [70.5%] male; 211 [83.1%] non-Hispanic white), germline mutations were identified in 41 (16.1%); 14 (5.5%) had mutations in syndromic RCC-associated genes (7 in FH, 3 in BAP1, and 1 each in VHL, MET, SDHA, and SDHB).
Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma.
Compared to patients with PBRM1+ BAP1+ tumors those with PBRM1- BAP1+ lesions were more likely to die of renal cell carcinoma (HR 1.39, p = 0.035), followed by those with PBRM1+ BAP1- and PBRM1- BAP1- tumors (HR 3.25 and 5.2, respectively, each p <0.001).
Furthermore, in three families we found three different variants in BAP1, one of which was a novel non-segregating missense variant (c.1502G>A, p.Ser501Asn) in a family with two brothers affected with RCC.