Background: The use of multi-gene panel testing (MGP) for hereditary breast cancer has been increasing. Currently, the indications for MGP depend on personal and/or family history of cancer, as tumor phenotype and patient characteristics for non-BRCA related cancers are not well described. The present study analyzed tumor characteristics of breast cancers associated with non-BRCA hereditary mutations. Methods: Institutional IRB-approved prospective databases from the International Society of Cancer Risk Assessment and Management (ISC-RAM) members were queried for patients with invasive breast cancer who underwent MGP between 2013-2017. Clinical and tumor characteristics for mutation carriers were analyzed using descriptive statistics and Pearson’s and Fisher’s Chi-Square analyses. Results: Of a total of 1,854 patients with invasive breast cancer who underwent MGP, 374 (20%) had a positive pathogenic gene mutation. Median age at diagnosis was 46 years (range: 22-85). Positive testing results were as follows: BRCA1: 77 (21%); BRCA2: 76 (20%); ATM: 45 (12%); CHEK2: 47 (12.5%); PALB2: 32 (8.5%); TP53: 16 (4.3%); MUTYH: 13 (3.5%); 68 (18.2%) patients tested positive for other genes (APC, BRIP1, BARD1, PTEN, STK11, CHD1, MLH, MSH, PMS, CDKN2A, NBN, NF1, RAD50, RAD51, SDHD, AXIN2, MITF, GALNT12, XRCC2). As expected, BRCA1 mutation was associated with triple negative breast cancer (p < 0.0001). The tumor characteristics of all other carriers were similar to those seen in BRCA2 carriers with two exceptions: MUTYH carriers were more likely to have invasive lobular cancers (p < 0.0001) and TP53 carriers were younger at diagnosis (p < 0.001) and more likely to have HER-2/neu positive cancers (p = 0.006). Conclusions: Our collected series of patients with non-BRCA hereditary breast cancers demonstrates specific tumor characteristics associated with TP53 and MUTYH mutations. Further exploration is warranted to expand this data set and further characterize cancers that are associated with low frequency genetic mutations. The frequency of ER positive tumors in these patients suggests that chemoprevention may be an important strategy in this population.