Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP variants associated with breast cancer risk show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors can affect the expressivity and penetrance of the disease. However, there are gaps in translating how individual genomic variation affects phenotypic presentation. The expansion of criteria for genetic testing and the increasing utilization of comprehensive genetic panels may enhance the identification of individuals carrying P/LP variants linked to hereditary breast cancer. Individualized risk assessment could facilitate the implementation of personalized risk-reduction strategies for these individuals. Preventive interventions encompass lifestyle modifications, chemoprevention, enhanced surveillance through breast imaging, and risk-reducing surgeries. This review addresses the current literature’s inconsistencies and limitations, particularly regarding risk factors and the intensity of preventive strategies for women with P/LP variants in moderate- and high-penetrance genes. In addition, it synthesizes the latest evidence on risk assessment and primary and secondary prevention in women at high risk of breast cancer.

Lynch syndrome is a genetic condition predisposing to cancer, particularly colorectal cancer and endometrial cancer, due to germline mutations in MisMatch Repair genes. More rarely, Lynch syndrome is the result of a constitutional MLH1 promoter methylation. This review summarizes the current knowledge about the role of this epigenetic mechanism in the Lynch syndrome. Universal Tumor Screening, performed on tumoral specimens to identify features suggestive of Lynch syndrome, shows the same features both in the case of sporadic cancers and Lynch syndrome-cancers due to a constitutional MLH1 methylation: microsatellite instability, deficiency of MisMatch Repair proteins, and methylation of MLH1 gene. Over the last few years, identifying methylation of MLH1 promoter on tumors was used to discern sporadic tumors from Lynch syndrome tumors: the methylation of the MLH1 promoter was usually explained as a somatic event and this could lead to a missed diagnosis of some Lynch syndrome cases. Therefore, establishing criteria to decide when to test patients for constitutional MLH1 methylation is urgent. In the case of microsatellite instability/deficiency of MisMatch Repair tumors with MLH1 methylation, a germline genetic test could be requested for all colorectal cancer patients aged 55 years or younger and all endometrial cancer patients younger than 50 years old, independently from family history. The prevalence of germline MLH1 epimutations is not precisely known and possibly underestimated. The associated cancer risk could be similar to that due to a MLH1 sequence variant. MLH1 epimutations could be secondary to other genetic defects and follow an autosomal dominant inheritance. On the contrary, primary epimutations are often “ de novo” events, and their transmission does not follow Mendelian rules.

Women carrying pathogenic/likely pathogenic (P/LP) variants in moderate- or high-penetrance genes have an increased risk of developing breast cancer. However, most P/LP variants associated with breast cancer risk show incomplete penetrance. Age, gender, family history, polygenic risk, lifestyle, reproductive, hormonal, and environmental factors can affect the expressivity and penetrance of the disease. However, there are gaps in translating how individual genomic variation affects phenotypic presentation. The expansion of criteria for genetic testing and the increasing utilization of comprehensive genetic panels may enhance the identification of individuals carrying P/LP variants linked to hereditary breast cancer. Individualized risk assessment could facilitate the implementation of personalized risk-reduction strategies for these individuals. Preventive interventions encompass lifestyle modifications, chemoprevention, enhanced surveillance through breast imaging, and risk-reducing surgeries. This review addresses the current literature's inconsistencies and limitations, particularly regarding risk factors and the intensity of preventive strategies for women with P/LP variants in moderate- and high-penetrance genes. In addition, it synthesizes the latest evidence on risk assessment and primary and secondary prevention in women at high risk of breast cancer.