Due to the rapidly reducing cost of next-generation sequencing, patients with breast cancer can choose not only BRCA1/2 sequencing but also low-cost multiple genes panel. However, in clinical practice, the impact and benefits of those multiple-gene test are not clear yet. The researchers selected 5026 patients with breast cancer from SEER, who had complete data for the retrospective cohort study, to understand their experience of multiple-gene or only BRCA1/2 sequencing. In this survey, from 2013 to 2015, the use of multiple gene sequencing increased from 25.6% to 66.5%, while BRCA1/2-only test declined from 74.4% to 33.5%, indicating the multiple-gene sequencing was gradually substituting for BRCA1/2-only. The detection rate of any pathogenic variants in multiple-gene sequencing was higher than BRCA1/2-only, but the detection rate of VUS in multiple-gene sequencing was higher than BRCA1/2-only, particularly in non-white patients. The test result of multiple-gene sequencing does not affect the decision-making of prophylactic mastectomy. According to this research, there were two limitations of multiple-gene sequencing in clinical utility, one was long turnaround time and another was marked difference in VUS rates by race and ethnicity.