Breast cancer (BC) remains a significant global health challenge with profound socioeconomic and health impacts. In Pakistan, BC is the leading cancer among women, accounting for 31.3 % of all female cancers [1]. The age-standardized (world) incidence and mortality rates are 34.2 and 18.6 per 100,000, respectively [1]. As the fifth most populous country globally, Pakistan has the highest mortality-to-incidence ratio and cumulative BC risk among South Asian countries [2]. This multifactorial disease is influenced by genetic predispositions, lifestyle factors, and hormonal and environmental exposures [3]. Notably, Pakistani women are diagnosed with BC nearly a decade earlier than their Asian and Caucasian counterparts [4], and are more likely to present with a triple-negative BC phenotype compared to Caucasian or non-Hispanic White women [5]. Moreover, the genetic landscape of BC in Pakistani patients differs markedly from that of other Asian populations [6], [7]. These unique characteristics suggest that the genetic and non-genetic risk factors for BC in Pakistani women may differ significantly from those in other populations.

Genetic anticipation is a phenomenon in which certain genetic disorders manifest at an earlier age and with increased severity in successive generations [8]. Although is well-documented in neurodegenerative disorders, genetic anticipation has also been observed in several hereditary cancers, including familial leukemia [9], Hodgkin’s and non-Hodgkin’s lymphoma [10], Lynch syndrome [11], and familial pancreatic cancer [12]. In BC, genetic anticipation has been reported in families harboring pathogenic variants (PVs) in BRCA2 [13], [14], as well as in both BRCA1 and BRCA2 (BRCA1/2) [15], [16], [17], [18], [19]. Women harboring BRCA1/2 PVs have an estimated 70 % cumulative risk of developing BC by age 80 and often exhibit an aggressive disease phenotype [20]. Additionally, approximately 10–20 % of familial BC patients are carriers of BRCA1/2 variants of uncertain significance, with reclassification probabilities ranging from 5 % to 95 % of these variants as PVs [21]. Notably, anticipation has also been documented in BC families without PVs in BRCA1/2 [14], [15], [16], [17].

While consensus exists regarding screening guidelines for average-risk women, recommendations for initiating screening in high-risk groups vary [22]. The National Comprehensive Cancer Network (NCCN) and the American Cancer Society (ACS) recommend starting BC screening 10 years prior to the age at which the youngest family member was diagnosed, but not before age 25 [22]. Findings from genetic anticipation studies are crucial for refining these screening guidelines and improving the management of familial BC.

Most studies on genetic anticipation in BC have been limited by small sample sizes (<100 families) [13], [14], [15], [16], [18], [23], [24], [25] and have primarily focused on Caucasian populations [8], [13], [14], [16], [17], [18], [19], [23], [24], [25]. To our knowledge, only one study from Asia has documented genetic anticipation in Korean familial BC patients [15]. Given the paucity of data, this study investigates the anticipation effect in familial BC patients from Pakistan. The objectives are to analyze: i) differences in ages at BC diagnosis between mother-daughter pairs; ii) differences in ages at BC diagnosis between mothers’ and daughters’ generations, including first-degree relatives affected with BC; and iii) BC risk in mothers’ and daughters’ generations.