Re-evaluating hereditary breast and ovarian cancer risk: clinical impact of updated multigene panel sequencing and genetic counseling

An increased lifetime risk of ovarian cancer is observed among women with a family history of ovarian cancer, with or without breast cancer, as well as among carriers of pathogenic germline variants in ovarian cancer (OC) predisposition genes. Over the past two decades, additional OC–associated genes beyond BRCA1/2 have been identified, highlighting the need for updated genetic evaluation in women previously classified as high-risk without a known PV to ensure correct diagnosis and prevent overtreatment. This retrospective, quality assurance cohort study aimed to evaluate whether updated multigene panel sequencing and genetic counseling improve risk stratification. All women enrolled in the OC surveillance program at Copenhagen University Hospital Herlev between 2018 and 2023 and received counseling prior to the implementation of the revised 2017 guidelines in Denmark, were included. Among 674 women (median age 40.9), 174 had a BRCA1 PV, 168 had a BRCA2 PV, 55 had PVs in moderate-risk genes, and 277 were enrolled based on family history of OC ± BC alone. Of these 277, 216 (78%) underwent updated genetic testing and counselling; 165 (76%) had no increased risk of OC and were released from gynecological surveillance. Over a mean follow-up of 48 months, none developed OC, and one developed BC, corresponding to a negative predictive value of 99% for the updated risk assessment. Updated genetic testing and counseling significantly improve risk stratification in women previously classified as increased risk of OC based solely on family history. This supports re-evaluation of at-risk women and families to guide appropriate surveillance, reduce unnecessary follow-up and interventions, and align clinical practice with evolving guidelines.