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

Sep 23, 2026

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Ovarian cancer prevention and early detection require better strategies for identifying women at elevated risk, enabling access to preventive care and reducing overall disease burden. Next-generation sequencing supports investigation of monogenic hereditary cancer predisposition genes, including ovarian cancer genes. Two cases demonstrate germline heterozygous pathogenic ATM variants, emphasizing management guidance for moderate-penetrance genes. Carriers show increased neoplasm risk, mainly breast and also ovarian cancer, yet evidence for benefit from risk-reducing bilateral salpingo-oophorectomy remains insufficient.

LanguageEnglish

CategoryHealthcare

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Abstract

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Methods and Results

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Introduction

Molecular Biology Reports (2025) 52:261 [https://doi.org/10.1007/s1](https://doi.org/10.1007/s1) 1033-025-10357-x Beyond the BRCA1/2 genes in ovarian cancer: the role of germline pathogenic variants in theATM gene Daniele Guadagnolo1 · Angelo Minucci2 · Antonella Chiavassa3 · Gabriella Gentile3 · Francesca Salvatori3 · Nader Khaleghi Hashemian1 · Giulia Maneri2 · Maria Piane4,5 · Simona Grotta6 · Paola Grammatico6 · Antonio Pizzuti1 · Daniele Santini3,7 · Laura De Marchis3,8 Received: 5 January 2025 / Accepted: 11 February 2025 / Published online: 21 February 2025 © The Author(s) 2025 Abstract 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 theATM 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. Keywords ATM · Hereditary Breast and Ovarian Cancer · Ovarian cancer · Cancer prevention · Moderate penetrance genes · Risk-Reducing Bilateral Salpingo-oophorectomy Introduction Daniele Guadagnolo and Angelo Minucci have contributed equally to this work. Ovarian cancer (OC) occupies the eleventh place for incidence among female cancers in western populations and has a significant health burden due to the late and non-specific symptoms and the absence of validated screening strategies * Laura De Marchis [laura.demarchis@uniroma1.it](laura.demarchis@uniroma1.it) 1 Department of Experimental Medicine, School of Medicine and Dentistry, Sapienza University of Rome, 00185 Rome, Italy 2 Departmental Unit of Molecular and Genomic Diagnostics, Fondazione Policlinico Gemelli IRCCS, Rome, Italy 3 Department of Radiological, Oncological and Pathological Science, School of Medicine and Dentistry, Sapienza University of Rome, 00161 Rome, Italy 4 Sant ‘Andrea University Hospital, 00189 Rome, Italy 5 Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, 00189 Rome, Italy 6 Laboratory of Medical Genetics, San Camillo-Forlanini Hospital, 00152 Rome, Italy 7 Department of Medico-Surgical Sciences and Biotechnology, Polo Pontino, Sapienza University of Rome, Rome, Italy 8 Oncology Unit, Department of Hematology, Oncology and Dermatology, Umberto I University Hospital, 00161 Rome, Italy that could allow early diagnosis. A woman’s life-time risk for ovarian cancer is about 1/70, 1.3%[1] Despite the important improvements in the treatment in the last decade, ovarian cancer remains the most lethal gynecologic malignancy [2] . A significant portion of cases of OC, accounting for more than 20%, appears to be associated with monogenic cancer susceptibility conditions, of which the majority (up to 90%) is due to hete

FAQs

Why is identifying high-risk women important in ovarian cancer prevention?

Risk identification enables access to preventive interventions that can reduce disease burden. The article notes that effective surveillance is limited, making early-stage detection challenging.

What did the case reports show about ATM variants in ovarian cancer?

Two ovarian cancer cases were reported in which a germline heterozygous pathogenic variant in the ATM gene was identified. One case relates to HBOC family history and the other to a late onset of neoplasms.

Is bilateral Salpingo-oophorectomy proven beneficial for ATM variant carriers?

The article states there is no well-established evidence of benefit in risk-reducing bilateral Salpingo-oophorectomy for carriers of heterozygous pathogenic ATM variants.

Sep 23, 2026

Uploaded by Aria