Simple SummaryThe NCCN Clinical Practice Guidelines are testing criteria used to identify high-risk individuals associated with an increased risk of breast, ovarian, pancreatic, and prostate cancer. The testing criteria have been recently modified in early 2023. In this study, we provided a real-world application of the updated criteria and their effect on germline mutation rates in Chinese high-risk breast cancer patients. An additional 6.4% (242/3797) of the patients were included after the revision; the mutation rates in these newly included patients were 2.1% and 2.5% forBRCA1/2and all six high-penetrance genes (BRCA1,BRCA2,CDH1,PALB2,PTEN, andTP53), respectively. Applying the updated criteria for genetic investigation would increase the number of positive detection, leading to potentially more patients. However, the balance between the resource and benefits requires further consideration.AbstractBackground: The National Comprehensive Cancer Network (NCCN) testing criteria for the high-penetrance breast cancer susceptibility genes, specificallyBRCA1,BRCA2,CDH1,PALB2,PTEN, andTP53, have been recently modified in 2023 to 2023 v.1. The following criteria have been changed: (1) from a person diagnosed with breast cancer at ≤45 to ≤50; (2) from aged 45–50 of personal breast diagnosis to any age of diagnosis with multiple breast cancers; and (3) from aged ≥51 of personal breast diagnosis to any age of diagnosis with family history listed in NCCN 2022 v.2. Methods: High-risk breast cancer patients (n= 3797) were recruited from the Hong Kong Hereditary Breast Cancer Family Registry between 2007 and 2022. Patients were grouped according to NCCN testing criteria 2023 v.1 and 2022 v.2. A 30-gene panel for hereditary breast cancer was performed. The mutation rates on high-penetrance breast cancer susceptibility genes were compared. Results: About 91.2% of the patients met the 2022 v.2 criteria, while 97.5% of the patients met the 2023 v.1 criteria. An extra 6.4% of the patients were included after the revision of the criteria, and 2.5% of the patients did not meet both testing criteria. The germlineBRCA1/2mutation rates for patients meeting the 2022 v.2 and 2023 v.1 criteria were 10.1% and 9.6%, respectively. The germline mutation rates of all 6 high-penetrance genes in these two groups were 12.2% and 11.6%, respectively. Among the additional 242 patients who were included using the new selection criteria, the mutation rates were 2.1% and 2.5% forBRCA1/2and all 6 high-penetrance genes, respectively. Patients who did not meet both testing criteria were those with multiple personal cancers, a strong family history of cancers not listed in the NCCN, unclear pathology information, or the patient’s voluntary intention to be tested. The mutation rates ofBRCA1/2and the 6 high-penetrance genes in these patients were 5.3% and 6.4%, respectively. Conclusion: This study provided a real-world application of the revision of NCCN guidelines and its effect on the germline mutation rate in the Chinese population. Applying the updated criteria for further genetic investigation would increase the positive detection rate, and potentially more patients would benefit. The balance between the resource and outcome requires careful consideration.