AbstractBackgroundGenetic testing plays an important role in guiding screening, diagnosis, and precision treatment of breast cancer (BC). However, the appropriate genetic testing criteria remain controversial. The current study aims to facilitate the development of suitable strategies by analyzing the germline mutational profiles and clinicopathological features of large‐scale Chinese BC patients.MethodsBC patients who had undergone genetic testing at the Sun Yat‐sen University Cancer Center (SYSUCC) from September 2014 to March 2022 were retrospectively reviewed. Different screening criteria were applied and compared in the population cohort.ResultsA total of 1035 BC patients were enrolled, 237 pathogenic or likely pathogenic variants (P/LPV) were identified in 235 patients, including 41 out of 203 (19.6%) patients tested only forBRCA1/2genes, and 194 out of 832 (23.3%) received 21 genes panel testing. Among the 235 P/LPV carriers, 222 (94.5%) met the NCCN high‐risk criteria, and 13 (5.5%) did not. While using Desai's criteria of testing, all females diagnosed with BC by 60 years and NCCN criteria for older patients, 234 (99.6%) met the high‐risk standard, and only one did not. The 21 genes panel testing identified 4.9% of non‐BRCAP/LPVs and a significantly high rate of variants of uncertain significance (VUSs) (33.9%). The most common non‐BRCAP/LPVs werePALB2(11, 1.3%),TP53(10, 1.2%),PTEN(3, 0.4%),CHEK2(3, 0.4%),ATM(3, 0.4%),BARD1(3, 0.4%), andRAD51C(2, 0.2%). Compared withBRCA1/2P/LPVs, non‐BRCAP/LPVs showed a significantly low incidence of NCCN criteria listed family history, second primary cancer, and different molecular subtypes.ConclusionsDesai's criteria might be a more appropriate genetic testing strategy for Chinese BC patients. Panel testing could identify more non‐BRCAP/LPVs thanBRCA1/2testing alone. Compared withBRCA1/2P/LPVs, non‐BRCAP/LPVs exhibited different personal and family histories of cancer and molecular subtype distributions. The optimal genetic testing strategy for BC still needs to be investigated with larger continuous population studies.