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Key Clinical Message: A rare missense mutation was identified as a reversion mutation using cancer genomic profiling and a suspected mechanism underlying resistance to olaparib in breast cancer. A 34‐year‐old woman with breast cancer and BRCA2: p.Gln3047Ter was treated with olaparib. After tumor progression, cancer genomic profiling testing using liquid biopsy revealed BRCA2 p.Gln3047Ter and p.Gln3047Tyr, with 48.9% and 0.37% allele frequency, respectively. These findings shed light on reversion mutation as a mechanism of resistance to olaparib in breast cancer. [ABSTRACT FROM AUTHOR]

Notch signaling plays various roles in cell-fate specification through direct cell–cell interactions. Notch receptors are evolutionarily conserved transmembrane proteins with multiple epidermal growth factor (EGF)-like repeats. Drosophila Notch has 36 EGF-like repeats, and while some play a role in Notch signaling, the specific functions of most remain unclear. To investigate the role of each EGF-like repeat, we used 19 previously identified missense mutations of Notch with unique amino acid substitutions in various EGF-like repeats and a transmembrane domain; 17 of these were identified through a single genetic screen. We assessed these mutants' phenotypes in the nervous system and hindgut during embryogenesis, and found that 10 of the 19 Notch mutants had defects in both lateral inhibition and inductive Notch signaling, showing context dependency. Of these 10 mutants, six accumulated Notch in the endoplasmic reticulum (ER), and these six were located in EGF-like repeats 8–10 or 25. Mutations with cysteine substitutions were not always coupled with ER accumulation. This suggests that certain EGF-like repeats may be particularly susceptible to structural perturbation, resulting in a misfolded and inactive Notch product that accumulates in the ER. Thus, we propose that these EGF-like repeats may be integral to Notch folding. [ABSTRACT FROM AUTHOR]