Background: HRR and microsatellite instability-high (MSI-H) alterations (alt) are typically mutually exclusive in pan-cancer cohorts. However, in PC 12.8% of BRCA1 and 3.4% of BRCA2 genomic alteration(alt) (Loss of function mutation or copy loss) co-occurred with MSI-H (PMID: 35772050) but were not associated with elevated genome-wide loss of heterozygosity (gLOH), suggesting that BRCA1/2 alt are likely ‘passenger’ events in the presence of MSI-H. further characterize this potential bystander phenomenon, we hypothesized that patients (pts) with HRR alt occurring in the context of hTMB will lack functional HRD signatures. Methods: We queried the Stand Up to Cancer (SU2C) East Coast Dream Team’s exome dataset (N=429) to identify pts with hTMB and at least monoallelic HRR alterations. Demographics, treatment, and outcome data were also collected. Adopting the approach per PMID: 34877933, we derived CSig3 (a COSMIC single-base-substitution mutational signature indicative of HR dysfunction [HRD]) and iHRD (a functional signature of HR deficiency developed by our group) in this subset to evaluate HRR functional activity. Results: 18 men with hTMB (>10mut/Mb) and concurrent HRR alt were identified in SU2C. Of those, 9 had biallelic, and 9 had monoallelic HRR alt. 22% had biallelic BRCA2, 22% had biallelic RAD and 39% had monoallelic BRCA2 alt. However, only 33% of these HRR-altered tumors were CSig3(+)/iHRD(+) (5 biallelic and 1 monoallelic HRR alt) and 67% were negative for both signatures (4 biallelic, 8 monoallelic HRR alt), indicating that the HRR alt in these instances are likely bystander events. In all of the CSig3(+)/iHRD(+) cases, TMB ranged between 10-20 mut/Mb, whereas when TMB was >20 mut/Mb, those tumors were invariably CSig3(-)/iHRD(-). None of these pts in the SU2C cohort were treated with Immune checkpoint inhibitors or PARPi. Conclusions: In PC pts with hTMB and concurrent HRR mutations, it is more likely that the HRR alteration is a ‘passenger’ event, and the likelihood increases as TMB rises above >20 mut/Mb. HRD signature (-) hTMB pts are unlikely to respond to PARPi monotherapy, even if they have a concurrent HRR alt. HR functional signatures such as CSig3 or iHRD could be utilized in treatment selection and to avoid diagnostic dilemmas.