In our study, we observed that the rs80359550 polymorphism in BRCA2 was strongly associated with breast cancer risk in the western population of Iran. These findings align with other studies, including those by Bayram et al. [6], who found significant associations between the HOTAIR rs920778 polymorphism and BC susceptibility in Turkish populations [6]. Similarly, Bayram et al. [7] identified the rs12826786 C > T polymorphism in HOTAIR as a key factor in BC risk and clinicopathological features in another Turkish cohort [7]. These studies further underline the role of genetic polymorphisms in shaping individual susceptibility to BC.

In contrast, we did not detect any association between the rs386833395 polymorphism and BC risk in our study population. This lack of association is similar to the findings of a Turkish study by Aydin et al. [8], which investigated the role of hTERT gene polymorphisms in BC risk. Although this study did not find any significant links between hTERT polymorphisms and BC risk, it supports the notion that genetic associations can vary significantly across different populations [8].

The current study aimed to examine the role of specific polymorphisms in breast cancer risk, focusing on the association between three SNPs—rs4135113, rs4135050, and rs4135066—and BC risk in a very selective subset of the Iranian population. According to our data, the rs80359550 and rs180177102 polymorphisms were strongly associated with BC risk in the western population of Iran. However, no detectable association was found for rs386833395, as the mutation was not observed in either the patient or control groups.

Breast cancer is considered one of the most significant challenges for healthcare systems, with the number of new BC cases increasing worldwide [3]. Late diagnosis is a major contributor to the high mortality rate among these patients [5]. Given the differences among populations based on ethnicity and geographic region, a specific genetic marker panel would facilitate early diagnosis for populations at genetic risk for BC [19] Many studies have reported the importance of genetic polymorphisms in an individual’s susceptibility to BC [20]. Germ line pathogenic variants in DNA repair system genes, such as PALB2, BRCA1, and BRCA2, are correlated with high BC risk [9, 14]. The BRCA1 and BRCA2 genes play a crucial role in double-stranded DNA break repair in response to DNA damage, and germ line mutations in these genes are commonly observed in BC [9, 21, 22]. The prevalence of the 185delAG mutation in BRCA1 and the 6174delT mutation in BRCA2 varies considerably across ethnic populations [9]. Mutation screening in these genes aids in identifying individuals who carry pathogenic variants and are at high risk for developing BC [23].

In our study, we examined the breast cancer susceptibility associated with two SNPs in BRCA1 (rs386833395) and BRCA2 (rs80359550) through a case-control study involving 335 BC patients and 354 healthy controls. We found a stronger association of rs80359550 with breast cancer development compared to previous reports [24]. In contrast, a Turkish study indicated that the rs386833395 polymorphism is not common in the Turkish population with early-onset BC [25]. However, as noted earlier, our results showed a strong association for rs80359550. In another Iranian study, the frequency of the 185delAG (rs386833395) mutation in BRCA1 and the 6174delT (rs80359550) mutation in BRCA2 was examined to assess their impact on BC risk. This study, which included 200 healthy controls, 250 sporadic BC cases, and 55 familial BC cases from southern Iran, found that these variants had a lower frequency in southern Iranian BC patients [26].

Like BRCA1 and BRCA2, the PALB2 gene is one of the ten genes associated with BC risk, with a frequency of 0.7 − 1.1% in familial BC cases [27]. PALB2 encodes a protein that binds and forms a multi-protein complex with BRCA2 and BRCA1, facilitating DNA repair in the homologous recombination pathway [28, 29]. Any germ line variant in the PALB2 gene that leads to an incomplete protein can impair the double-strand break repair system, increasing BC risk [28, 29]. Over the past two decades, population-based studies have indicated that pathogenic variants in PALB2 account for approximately 0.83–2% of familial BC cases in Spanish and African populations [30,31,32]. Our study provides evidence that the PALB2 polymorphism, rs180177102, is strongly associated with BC risk (OR = 0.012). (OR = 0.012).

This study has several limitations that should be acknowledged. While the sample size is significant, it may still limit the generalizability of the findings, particularly for low-frequency polymorphisms. Additionally, the study focused solely on a subset of the Iranian Kurdish population, which may not reflect the genetic diversity of other populations. The investigation was restricted to a limited number of SNPs and did not include other potential genetic variants or functional analyses to elucidate biological mechanisms. Environmental and lifestyle factors were not considered, and the case-control design may introduce biases. Moreover, breast cancer subtype-specific analyses were not conducted, which could have provided more detailed insights into genetic predispositions for different forms of the disease. Future studies should address these gaps by expanding the sample size, genetic scope, and considering additional factors such as the environment and cancer subtypes.