Multiple Primary Cancers as an Independent Criterion for Germline Testing: Comparison with Guideline-Based Criteria

<b>Background</b>: Multiple primary cancers (MPCs) often indicate an underlying hereditary predisposition. Current genetic testing guidelines mainly target specific cancer types, potentially missing MPC patients who do not meet these criteria. This study evaluated the utility of MPCs as an independent criterion for germline genetic testing by comparing the pathogenic variant (PV) diagnostic yields of guideline-based and MPC-based testing. <b>Methods</b>: Between June 2022 and June 2023, we prospectively enrolled 62 patients diagnosed with two or more pathologically confirmed primary cancers. Patients were classified into a Guideline group (<i>n</i> = 29), which met NCCN/ACMG testing criteria, and a Non-Guideline group (<i>n</i> = 33) classified solely on the MPC status. Germline testing was performed using a 25-gene hereditary cancer panel and by BRCA1/2 next-generation sequencing. <b>Results</b>: Pathogenic variants were identified in four patients (6.5%): two in the Guideline group (<i>CHEK2</i>, <i>BRCA2</i>) and two in the Non-Guideline group (<i>ATM</i>, <i>TP53</i>). Diagnostic yields were similar in the two groups (6.9% vs. 6.1%, respectively, <i>p</i> = 0.763). Of eight patients with ≥3 primary cancers, one patient (12.5%) had a clinically significant <i>TP53</i> deletion without meeting Li-Fraumeni syndrome criteria. All PV-positive patients had a family history of cancer. Variants of uncertain significance were identified in 25 (40.3%) of the 62 study subjects. <b>Conclusions</b>: Germline genetic testing based solely on MPC had a diagnostic yield comparable to guideline-based testing. MPC could be considered as an independent criterion for genetic testing to improve the identification of a hereditary cancer predisposition.