Search

Background: BRCA1:c.5017_5019del (p.His1673del) is a founder variant relatively frequent in Northern Italy. Despite previous suggestion of pathogenicity, variant classification in public databases is still conflicting, needing additional evidence. Methods: Maximum likelihood penetrance of breast/ovarian and other cancer types was estimated using full pedigree data from 53 informative Italian families. The effect of the variant on BRCA1‐ABRAXAS1 interaction was assessed using a GFP‐fragment reassembly‐based PPI assay. Results were combined with additional data from multiple sources to classify the variant according to ACMG/AMP classification rules specified for BRCA1/2. Results: Variant‐carriers displayed increased risk for ovarian cancer (HR = 33.0, 95% CI = 7.0–155.0; cumulative risk at age 70 = 27.6%, 95% CI = 12.6–40.0%) but not for breast cancer (HR = 0.7, 95% CI = 0.2–2.2). An increased risk of uterine cancer (HR = 8.0, 95% CI = 1.03–61.6) emerged, warranting further evaluation. Likelihood‐ratio in favor of pathogenicity was 98898642.82 under assumption of standard BRCA1 breast and ovarian penetrance, and 104240832.84 after excluding breast cancer diagnoses (based on penetrance results). Functional analysis demonstrated that the variant abrogates the BRCA1‐ABRAXAS1 binding, supporting the PS3 code assignment within the ACMG/AMP rule‐based model. Collectively, these findings allowed to classify the variant as pathogenic. Conclusion: Pathogenicity of BRCA1:c.5017_5019del(p.His1673del) has been confirmed; however, breast cancer risk in Italian families is not increased, unlike in families from other countries and in carriers of most BRCA1 pathogenic variants. The knowledge of atypical risk profiles for this and other variants will pave the way for personalized management based on specific genotype. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Germline pathogenic variants (PV) of the PALB2 tumor suppressor gene are associated with an increased risk of breast, pancreatic, and ovarian cancer. In previous research, PALB2‐associated breast cancer showed aggressive clinicopathological phenotypes, particularly triple‐negative subtype, and higher mortality regardless of tumor stage, type of chemotherapy nor hormone receptor status. The identification of this germline alteration may have an impact on clinical management of breast cancer (BC) from the surgical approach to the systemic treatment choice. We herein report the case of a patient with a germline PV of PALB2, diagnosed with locally advanced PD‐L1 positive triple‐negative BC, who progressed after an immune checkpoint inhibitor (ICI)‐containing regimen and then experienced a pathologic complete response after platinum‐based chemotherapy. This case report hints a major role of the germline PALB2 alteration compared to the PD‐L1 expression as cancer driver and gives us the opportunity to extensively review and discuss the available literature on the optimal management of PALB2‐associated BC. Overall, our case report and review of the literature provide additional evidence that the germline analysis of PALB2 gene should be included in routine genetic testing for predictive purposes and to refine treatment algorithms. [ABSTRACT FROM AUTHOR]