Background: FLCN is a tumor suppressor gene associated with cutaneous hair follicle development. FLCN germline mutations are linked to inherited chrRCC in the Birt-Hogg-Dube (BHD) syndrome. We queried whether clinically sporadic chrRCC featured FLCN mutations by comparing the genomic profiles of chrRCC with nonchrRCC. Methods: 109 chrRCC and 5,862 nonchrRCC underwent hybrid-capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. PD-L1 expression was determined by IHC (Dako 22C3). Results: Patients (pts) with chrRCC were more frequently female (37 [34%] vs. 1,817 [31%]) and younger than pts with nonchrRCC (median age 58 vs 62 years, p <.0001). None of the submitted clinical records in the chrRCC cases listed signs of BHD syndrome. FLCN GA were identified in the nonchrRCC cases only at 2.3% with 37% of the GA being germline. 1/109 (0.9%) of chrRCC featured a germline FLCN GA. GA/tumor were slightly higher in nonchrRCC vs chrRCC (3.6 vs 2.4; NS). There were no significant differences in gLOH, genomic signatures or ancestry between the groups. GA more frequent in chrRCC included TP53, RB1, PTEN. GA more frequent in the nonchrRCC included VHL, BAP1, PBRM1, SETD2, CDKN2A/B, ARID1A, NF2, PIK3CA and TERT. Biomarkers of immune checkpoint inhibitor (ICPI) drug response revealed higher mean TMB, TMB ≥10 mutations/Mb and PBRM1 inactivating mutation frequencies in the nonchrRCC than the chrRCC indicating possible differences in IO drug response. Conclusions:FLCN mutations that are associated with familial incidence of chrRCC are rarely associated with sporadic chrRCC. Sporadic chrRCC has a substantially different genomic profile from nonchrRCC and appears to harbor fewer opportunities for both targeted and immunotherapies.