Tyrer-Cuzick Lifetime Risk is Not Associated with Non-BRCA1/2 Pathogenic Variants for Breast Carcinoma

<title>Abstract</title> <bold>Purpose: </bold>The Tyrer-Cuzick lifetime risk score (TC LR) is used to estimate the probability of an unaffected female patient developing breast cancer as well as their likelihood of carrying a <italic>BRCA1/BRCA2 </italic>pathogenic variant (PV), considering factors such as family history, personal history, and breast density. The purpose of this study is to determine if TC LR is associated with non-<italic>BRCA1/2 </italic>PVs. <bold>Methods:</bold> A population of 964 patients, enrolled from 2019-2022, were evaluated for 12 PVs and variants of unknown significance (VUS) using lab agnostic genetic testing. TC LR scores were compared between the three patient cohorts - <italic>BRCA </italic>PVs, non-<italic>BRCA</italic> PVs, and PV negative, using Kruskal-Wallis test and DSCF adjustment for multiple comparisons. Chi-square test and logistic regression were used to compare the groups. <bold>Results:</bold> This study found an average TC LR of 7.71%. The presence of PVs and VUS was evaluated, with 12.03% of patients were found to have a PV (average TC LR 8.98%). Out of those with PVs, 52% had non-BRCA1/2 PVs (average TC LR 5.47%). A total of 102 patients (10.58%) had a VUS (average TC LR 8.29%). <bold>Conclusion:</bold> TC LR scores were found to be low in patients with non-BRCA1/2 PVs. The study suggests that the decision for genetic testing should not be influenced by TC LR but should be based on individual patient’s family history, NCCN guidelines, or the TC genetic risk score.