Clinicopathological Characteristics of Ovarian and Breast Cancer in PALB2, RAD51C, and RAD51D Germline Pathogenic Variant Carriers

<b>Background/Objectives:</b> Germline pathogenic variants (GPVs) in <i>PALB2</i>, <i>RAD51C</i>, and <i>RAD51D</i> increase breast cancer (BC) and ovarian cancer (OC) risk. Limited data on clinicopathological characteristics of BC and OC in women with these GPVs hamper guideline development. Therefore, this study aims to describe these characteristics in a consecutive series of female <i>PALB2</i>, <i>RAD51C</i>, and <i>RAD51D</i> GPV carriers. <b>Methods</b>: Women with a <i>PALB2</i>, <i>RAD51C</i>, or <i>RAD51D</i> GPV determined before July 2023 at the University Medical Center Groningen were included. Cancer diagnoses were obtained through linkage with the Dutch Nationwide Pathology Databank (Palga). Median onset age and histopathological subtypes were compared to the data of The Netherlands Cancer Registry (NCR). <b>Results</b>: Among 164 GPV carriers (125 <i>PALB2</i>, 30 <i>RAD51C</i>, and 9 <i>RAD51D</i>), 54 BC and 6 OC cases were identified. The median BC onset age was 52 (<i>n</i> = 50), 71 (<i>n</i> = 3), and 43 years (<i>n</i> = 1) for <i>PALB2</i>, <i>RAD51C</i>, and <i>RAD51D</i>, respectively, compared with 62 years in the NCR. No BC histological subtype differences were observed in <i>PALB2</i> carriers. The populations of <i>RAD51C</i> and <i>RAD51D</i> carriers were too small to compare to NCR data. No OC cases occurred in <i>PALB2</i> carriers. The median OC onset age was 66 (<i>n</i> = 4) and 56 years (<i>n</i> = 2) for <i>RAD51C</i> and <i>RAD51D</i> carriers, respectively, versus 67 years in the NCR. All <i>RAD51D</i> carriers had high-grade serous carcinoma, compared to 51.5% in the NCR. <b>Conclusions</b>: Differences in onset age and histological subtypes were observed between GPV carriers and national data. Further research on cancer characteristics is needed to optimize counseling and cancer prevention in these women.