Background: Germline genetic testing for hereditary cancer syndromes is essential to the management of patients with cancer, providing information with both therapeutic implications and guidance for preventative strategies for patients and at-risk family members. BRCA1 and BRCA2 are the most common genes with deleterious mutations associated with increased risk of developing hereditary breast, ovarian, prostate and pancreatic cancers. The objective of this study was to explore the prevalence of germline BRCA1 and BRCA2 mutations in individuals with known cancer compared to those with only a family history of cancer in a real-world patient population. Methods: Real-world clinical and genomic data were reviewed for 12,270 consecutive individuals referred to a clinical laboratory for BRCA1 and BRCA2 sequencing and copy number variant analysis. Clinical data were ascertained from testing requisition forms completed by healthcare providers. Germline variants in BRCA1 and BRCA2 were identified by next-generation sequencing. The incidence of pathogenic and likely pathogenic variants (PVs) were calculated for each gene, patient cohort and four common cancer types: breast, ovarian, prostate, and pancreatic. Statistical analysis was performed using chi squared and Fisher’s exact tests. Results: Among the 12,270 individuals referred for germline testing for BRCA1 and BRCA2, the majority were female (11,233, 91.5%). A large proportion of patients (9271, 75.6%) had a family history of breast, ovarian, pancreatic or prostate cancer. A total of 2506 patients (20.4%) had a personal history of one of these cancers. For 493 (4.0%), the exact indication for testing was unknown. The median age of patients with a personal history of cancer was 62 years (range: 18 to 95), significantly higher than the median age of patients with a family history of cancer (41 years, range: 3 to 89) (p < 0.0001). For the 2506 patients who reported a personal history of cancer, the most common cancer was breast (1919, 76.6%) followed by prostate (261, 10.4%), ovarian (253, 10.1%), and pancreatic (107, 4.3%). Testing identified 561 PVs, 243 in BRCA1 and 318 in BRCA2. PVs were identified significantly more often in patients with a family history compared to a personal history of breast cancer (4.4% vs 4.2%; p = 0.009) and pancreatic cancer (4.8% vs 2.8%; p = 0.03). Conclusions: Our data show that the prevalence of pathogenic or likely pathogenic variants in BRCA1 and BRCA2 is higher in individuals with a family history of breast and pancreatic cancers than in individuals with a personal history of these cancers. These results corroborate the utility of germline testing in identifying individuals with an inherited predisposition to cancer regardless of having a personal history of cancer, in a real-world setting.