Background: Broad-based germline multi-gene panel testing (MGPT) for inherited predisposition has become increasingly common for cancer patients. Both indications for germline testing and the spectrum of genes on MGPT have expanded. We sought to examine the frequency of an unexpected pathogenic/likely pathogenic variant (P/LPV) in patients with a variety of solid and hematologic malignancies undergoing MGPT. Methods: A retrospective review of patients with a history of cancer who underwent MGPT at a single institution from 2015 to 2021 with MGPT of > 20 cancer predisposition genes. Low penetrance genes and genes with a recessive inheritance pattern were excluded. Deidentified pedigrees were analyzed by genetic counselors for clinical diagnostic criteria and gene-specific national testing guidelines to determine whether clinical suspicion of the P/LPV was present. Results: 10,975 cancer patients underwent MGPT. 1,180 (10.9%) patients were found to have > 1 P/LPV in a moderate or highly penetrant cancer susceptibility gene. 357 (3.3%) of the P/LPV were unexpected based on patient’s personal cancer history alone. 208 (1.9%) of the P/LPV remained unexpected after patient and family cancer histories were considered. Most common cancer subtypes with an unexpected P/LPV were breast [1.5% (83/5691)], prostate [2.1% (28/1300)], colorectal [2.2% (18/823)], ovarian/fallopian [1.7% (13/781)] and uterine [ 2.8% (10/352)] cancer. Most frequent unexpected P/LPV were PMS2 (n = 19), MITF (n = 18), ATM (n = 18), BRIP1 (n = 17), CHEK2 (n = 14), HOXB13 (n = 13), SDHA (n = 12), BRCA2 (n = 7), MSH6 (n = 7), SDHC (n = 7), TP53 (n = 7), and PALB2 (n = 6). No predictor of having an unexpected P/LPV was identified in multivariable logistic regression analysis. Low penetrance or recessive variants were found in 521 (4.8%) patients. Variants of uncertain significance (VUS) were found in 3,774 (35.0%) patients. Conclusions: This large retrospective analysis of cancer patients undergoing MGPT identified an overall rate of 1.9% of P/LPV in actionable cancer predisposition genes. Findings were more often unexpected (3.3%) when considering only the patient cancer history, endorsing the importance of family cancer history for consideration of more targeted genetic testing. Identification of moderate or highly penetrant P/LPV in cancer patients is increasingly important in guiding treatment decisions, cancer screening in survivors and testing of at-risk family members. These findings may justify consideration of broader MGPT panels especially when family cancer history is uncertain or unavailable. MGPT also detected a high rate of VUS, reinforcing the importance of physician education to ensure appropriate interpretation and management.