Beyond the BRCA1/2 genes in ovarian cancer: the role of germline pathogenic variants in the ATM gene.

Background: Ovarian Cancer (OC) prevention and early-stage detection represents a challenge due to the lack of effective surveillance. The identification of high-risk women is crucial as it provides access to prophylactic oophorectomy and reduces disease burden. Next-Generation Sequencing approaches enable the investigation of several genes associated with monogenic hereditary cancer predisposition, including ovarian cancer. For family members of patients affected by ovarian cancer without identification of a germline pathogenic variant, despite the increased empirical risk (3 times) of ovarian cancer incidence, prophylactic surgery is not indicated but may be suggested as the only efficient strategy.

Methods and results: We hereby present 2 cases of OC in which a germline heterozygous pathogenic variant in the ATM gene was identified: the first in the contest of Hereditary Breast and Ovarian Cancer (HBOC) family history and, in the other one, a late onset of neoplasms, to underline the importance of defining guidelines and management of moderate penetrance genes variants also for ovarian cancer prevention.

Conclusions: Carriers of heterozygous pathogenic variants in the ATM gene have an increased risk of neoplasms incidence, mostly breast but also of OC with an absolute estimated risk of 2-3 times greater than the general population. For these patients there is not well-established evidence of benefit in risk reducing bilateral Salpingo-oophorectomy.