| Abstract | Individuals who carry pathogenic variants in either Breast Cancer Gene 1 (BRCA1) or Partner and Localizer of BRCA 2 (PALB2) protein have an increased risk of developing breast cancer. Multiple variations of unknown significance (VUS) have been documented within the coiled-coil region of each protein. In this study, we analyzed the structural effects of five proline VUS within the binding region of BRCA1 and PALB2. We hypothesize the proline variants will inhibit coiled-coil formation and, in turn, disrupt interaction between BRCA1 and PALB2. Each coiled-coil construct was generated in vitro and its structure analyzed using circular dichroism both individually and in the presence of its wild-type binding partner. All proline variants affected the structure of BRCA1, which is suggestive of their pathogenicity. Future studies may aim to correlate structural effects with function impact to determine a threshold of structural change that can be withstood before a variant is pathogenic. |
