A BRCA1 Coiled-Coil Domain Variant Disrupting PALB2 Interaction Promotes the Development of Mammary Tumors and Confers a Targetable Defect in Homologous Recombination Repair.

Abstract

The <i>BRCA1</i> tumor suppressor gene encodes a multidomain protein for which several functions have been described. These include a key role in homologous recombination repair (HRR) of DNA double-strand breaks, which is shared with two other high-risk hereditary breast cancer suppressors, BRCA2 and PALB2. Although both BRCA1 and BRCA2 interact with PALB2, <i>BRCA1</i> missense variants affecting its PALB2-interacting coiled-coil domain are considered variants of uncertain clinical significance (VUS). Using genetically engineered mice, we show here that a BRCA1 coiled-coil domain VUS, <i>Brca1</i> p.L1363P, disrupts the interaction with PALB2 and leads to embryonic lethality. <i>Brca1</i> p.L1363P led to a similar acceleration in the development of <i>Trp53</i>-deficient mammary tumors as <i>Brca1</i> loss, but the tumors showed distinct histopathologic features, with more stable DNA copy number profiles in <i>Brca1</i> p.L1363P tumors. Nevertheless, <i>Brca1</i> p.L1363P mammary tumors were HRR incompetent and responsive to cisplatin and PARP inhibition. Overall, these results provide the first direct evidence that a BRCA1 missense variant outside of the RING and BRCT domains increases the risk of breast cancer. SIGNIFICANCE: These findings reveal the importance of a patient-derived BRCA1 coiled-coil domain sequence variant in embryonic development, mammary tumor suppression, and therapy response.<i>See related commentary by Mishra et al., p. 6080</i>.