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Insights into genetic modifiers of breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants

Hereditary Cancer in Clinical Practice volume 23, Article number: 15 (2025) Cite this article

Abstract

Pathogenic variants in BRCA1 and BRCA2 are associated with an increased risk of developing several types of cancer, including breast cancer. However, the risk varies by other environmental and genetic factors present in carriers of mutation. To understand the value of these factors more clearly, a number of common genetic susceptibility variants have been studied through genome-wide association studies as potential genetic risk modifiers for BRCA1 and BRCA2 pathogenic variants carriers. Several studies have identified specific polymorphisms that may influence the risk of breast cancer development, either by increasing or reducing susceptibility. These variants are implicated in biological pathways such as DNA damage repair, hormonal regulation or cell proliferation. The identification and understanding of key genetic modifiers may provide valuable insights into development of personalized prevention, targeted therapies and screening strategies for high-risk individuals. This review presents the overview of known genetic risk modifiers for carriers of BRCA1 and BRCA2 pathogenic variants, their potential impact on risk, and their functional roles. Furthermore, it highlights the need for further research directions, including understanding the biological role of genetic modifiers in cancer development and the refinement of risk assessment models.

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Introduction

Breast cancer is the most common cancer in women worldwide. Approximately 2,3 million women are diagnosed with breast cancer each year [1]. It ranks as the fifth leading cause of cancer-related deaths globally, accounting for 685,000 fatalities [2]. Pathogenic variants in the BRCA1 and BRCA2 genes are associated with increased risk of developing breast cancer. The life-time risk of breast cancer for carriers of BRCA1 and BRCA2 pathogenic variants is about 65% and 45%, respectively [3, 4]. This risk can be influenced by a variety of specific factors. There are numerous studies investigating the impact of reproduction and environmental factors on the cancer penetrance among BRCA1/2 mutation carriers [5,6,7,8]. Moreover, common genetic variants have also been reported to modify that penetrance [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30]. As a result, women with the same mutation may develop cancer – or remain unaffected – depending on the additional genetic variants they carry. The aim of this study is to review and summarize the existing data on genetic modifiers of breast cancer risk in female BRCA1 and BRCA2 pathogenic variants carriers. It also emphasizes the value of research focused on genetic modifiers.

Methodology

The literature search was conducted in November 2024, and articles published from 2003 to 2024 were included in the review. The search terms comprised ‘BRCA1 modifiers breast cancer’, ‘BRCA2 modifiers breast cancer’, ‘BRCA1 genetic modifiers’, ‘BRCA2 genetic modifiers’, ‘BRCA1 modifiers GWAS’, ‘BRCA2 modifiers GWAS’, ‘BRCA1 CIMBA’, ‘BRCA2 CIMBA’. Boolean operator ‘AND’ was used to combine terms. A search was conducted using the PubMed database.

The detailed results of literature search strategy are shown in Fig. 1. A systematic search of papers was conducted according to established criteria to identify studies on genetic modifiers affecting breast cancer risk in carriers of PV in the BRCA1 and BRCA2 genes. The initial literature search found 2323 articles that met the basic search criteria. At the first stage, duplicates and articles unrelated to the topic of the study were eliminated, resulting in the removal of 2150 papers. The remaining 172 articles were subjected to a detailed evaluation, which resulted in the exclusion of publications that did not meet the specified inclusion criteria. Articles not available in full text and papers published in a language other than English were rejected. In addition, review articles and meta-analyses were excluded to focus on original research. Furthermore, papers that analyzed only male PV carriers and articles focusing on outcomes unrelated to breast cancer were excluded. Studies that used non-BRCA1/2 cases/controls were also removed, as well as papers that did not show any significant association between the analyzed genes and cancer risk.

Finally, the compilation of the 37 selected articles formed the basis of this review, and the results of these studies were presented to highlight the genetic modifiers of breast cancer risk in carriers of PV in the BRCA1 and BRCA2 genes. The analysis of these studies provided a better understanding of how various genetic factors can modify the risk of developing breast cancer in this group of individuals.

Fig. 1
figure 1

Strategy used to identify literature about genetic modifiers

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Genome wide-association studies

A number of common polymorphisms in candidate genes have been studied as a potential factors that may modify breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants. These studies have focused on genes considered functionally significant for the disease or those that interact with BRCA1 and/or BRCA2 genes. Knowledge of these risk modifiers could enable the more specific prediction of breast cancer progression in mutation carriers. Furthermore, they may result in the development of new therapies [31].

Previous large-scale association studies conducted by the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) have provided evidence of such breast cancer risk modifiers [31]. These studies examined common genetic variants which have been identified through genome-wide association studies (GWAS) as being linked to breast cancer risk in general population [32,33,34]. A genome-wide association study proceed in several steps (Fig. 2) [35, 36]. Through GWAS, copy-number variants (CNVs) or sequence variations in the human genome can be analysed, although single-nucleotide polymorphisms (SNPs) constitute the most frequently studied genetic variants in such studies [35]. GWAS is most often conducted by using pre-existing resources – disease-specific cohorts or biobanks. The selected cohort is divided into study and control group. The homogeneity of the study group in terms of the analysed feature is. Genotyping of individuals is usually performed using microarrays for common variants or, less frequently, using next-generation sequencing methods – whole exome sequencing (WES) or whole genome sequencing (WGS). Genotyping is carried out in several stages. First, in “discovery study”, a small proportion of the samples from cases and controls are tested. Then, SNPs that show the most significant associations with disease risk are retested in subsequent studies involving larger group. In the third phase, the study group expands significantly and may consist of tens of thousands of participants. After three phases of genotyping, the SNPs showing the strongest association are selected as markers that may influence disease. Typically, in GWAS, association testing is done by using linear or logistic regression models. Markers selected in study are further evaluated by mapping and performing functional studies to assess the association with the disease. The preliminary association should be replicate in an independent cohort. The last stage of study focuses on the validation of detected associations. The standard significance threshold for GWAS is p-value of 5.0 × 10− 8 [37].

Fig. 2
figure 2

Steps of conducting GWAS

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Genetic variants associated with breast cancer risk for BRCA1 pathogenic variants

The risk of developing breast cancer in carriers of pathogenic variants in the BRCA1 gene may be caused not only by the occurrence of mutation, but also by genetic modifiers. There is evidence that specific variants in some genes may influence the penetrance of breast cancer in BRCA1 mutation carriers. Numerous studies have focused on investigating SNPs which are located within genes being important in cellular processes, such as the regulation of cell growth or DNA repair [38].

One of the SNPs examined by CIMBA was a polymorphism of the apoptosis-related gene CASP8 (rs1045485). It was found that carriers of mutations in the BRCA1 gene with the ‘CC’ genotype at this locus have a reduced risk of breast cancer [39]. Another study showed that SNP c.1298 A > C in MTHFR gene may also reduce the risk. Genotypes ‘AC’ and ‘CC’ were associated with two-fold decreased breast cancer risk in Polish women carrying BRCA1 mutations [22]. Other genes whose polymorphisms have been identified as associated with a lower risk of breast cancer in BRCA1 mutation carriers are ANKLE1 (rs2363956), SNRPB (rs6138178), VEGF (rs3025039), TERT (rs2180341) and PTHLH (rs10771399) (Table 1).

Table 1 SNPs found to be associated with reduced breast cancer risk for BRCA1 pathogenic variants carriers
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There is evidence that benign variants in BRCA1 may also modify cancer risk among BRCA1 PV carriers. Cox et al. showed that women with the rare allele of SNP rs16942 on the wild-type copy of BRCA1 exhibited a reduced risk of breast cancer [19]. Another study reported that an intron variant of BRCA1 (rs5820483) is associated with exon 11 isoform expression, alternative splicing and the risk of developing breast cancer in BRCA1 PV carriers. Ruiz de Garibay et al. confirmed that effect in mouse cells, suggesting that disruption of BRCA1 exon 11 splicing modifies the cancer risk linked to pathogenic BRCA1 variants [40].

Variants increasing breast cancer risk have also been investigating. The ‘T’ allele of the SNP c.1630 C > T in PHB (rs6917) has been found to be associated with a two-fold increased breast cancer risk in Polish population [41]. The SNP rs6602595 in CAMK1D gene have also been reported as a modifier increasing breast cancer risk in BRCA1 pathogenic variants carriers [29]. There is also evidence that a non-synonymous polymorphism in IRS1 modifies breast cancer risk among BRCA1 PV carriers. Ding et al. reported that the variant of IRS1 (rs1801278), which interacts with insulin-like growth factor (IGF1R) and insulin receptor (IR), is associated with two-fold increased risk of developing breast cancer in BRCA1 class 2 mutation carriers [42]. Polymorphisms in the BABAM1 (rs8170), TERT (rs10069690), TCF7L2 (rs11196174), MDM4 (rs2290854), MTHFR (rs1801133) and ESR1 (rs2046210, rs9397435) likewise may increase the risk of breast cancer (Table 2).

Table 2 SNPs found to be associated with higher breast cancer risk for BRCA1 pathogenic variants carriers
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Breast cancer in individuals with BRCA1 PV is primarily ER-negative [45]. As a result, SNPs associated with ER-positive breast cancer in the general population, which account for most susceptibility variants identified through GWAS, are unlikely to affect the risk in BRCA1 PV carriers. Therefore, several studies have examined the association of genetic modifiers with the risk of tumour subtypes defined by ER-status. Notably, associations with ER-negative tumours—but not ER-positive tumours—have been confirmed for rs8170 in BABAM1, rs67397200 in BABAM [43], rs1045485 in CASP8 [46] and rs3817198 in LSP1 [47], among others (Table 3).

Table 3 SNPs found to be associated with Estrogen receptor status in breast cancer among BRCA1 and BRCA2 pathogenic variants carriers
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Even though SNPs are the primary focus of genetic modifier studies, copy number variants (CNVs) are also considered in such research, but their contribution is relatively unknown. Recent study suggests that deleterious variants in SULT1A1 may alter the breast cancer risk in carriers of BRCA1 mutation. The findings show that deletions in SULT1A, a gene encoding sulfotransferase 1A1 responsible for catalyse the sulfate conjugation of hormones, drugs and xenobiotics, may reduce the risk in BRCA1 PV carriers [48]. Moreover, another genome-wide CNVs analysis have reported that deletions in GTF2H2 are linked to a reduced risk of breast cancer. Since GTF2H2 is involved in nucleotide excision repair (NER), this result suggests that NER disruption may provide protection against the effects of a BRCA1 pathogenic variants [49].

For BRCA1 PV carriers, polymorphisms in ANKLE1 (rs2363956), BABAM1 (rs8170), TERT (rs10069690) and ESR1 (rs2046210, rs9397435) reached GWAS significance threshold (p-value < 5.0 × 10− 8).

Genetic variants associated with breast cancer risk for BRCA2 pathogenic variants

Breast cancer risk associated with mutations in the BRCA2 gene, as with the BRCA1 gene, can be altered by genetic modifiers. In addition, for the BRCA2, more genes variants have been identified that may influence breast cancer penetrance in mutation carriers.

Several studies have shown a modifying effect of the RAD51 c.135G > C (rs1801320) polymorphism on the risk of breast cancer in carriers of pathogenic variants in BRCA2 [14, 50]. It has been found that mutation carriers with ‘CC’ genotype at this locus are at three-fold increased risk of developing breast cancer compared with the ‘GG’ genotype [14]. Another study presents that the variants in TOX3/TNRC9 (rs3803662) and FGFR2 (rs2981582) may also increase the risk of breast cancer in BRCA2 mutation carriers. Moreover, it has been considered that for the combined effect of the two loci, the absolute risk of developing disease ranges from 41% for individuals with no risk alleles to 70% for those carrying four risk alleles [15]. It also has been proven that common variant in ALDH2 (rs10744777) may modify the lifetime risk of breast cancer for BRCA2 mutation carriers. Recent study has shown that the ‘TT’ genotype of the ALDH2 (rs10744777) variant combined with the BRCA2 p.K3326* variant increases the breast cancer risk among carriers by 1,72-fold [30]. There is likewise evidence that carriers with both BRCA1/2 pathogenic variants and mutations in PPARGC1A, a gene involved in energy metabolism regulation, may develop breast cancer at a significantly younger age [51]. An association with higher risk of developing breast cancer in BRCA2 pathogenic variants carriers has also been demonstrated for the polymorphisms in LSP1 (rs3817198), MAP3K1 (rs889312), LOC134997 (rs9393597) and FBXL7 (rs12652447). There is additionally evidence of association for SNPs in SMAD3 (rs3825977, rs7166081), EMBP1 (rs11249433), SLC4A7/NEK10 (rs4973768), FGF10/MRPS30 (rs10941679), FGF13 (rs619373) and ESR1 (rs9397435) (Table 4).

Table 4 SNPs found to be associated with higher breast cancer risk for BRCA2 pathogenic variants carriers
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In a recent study it has been found that a truncating variant of RAD52 (rs4987207) is significantly associated with reduced breast cancer risk in BRCA2 mutation carriers [9]. Moreover, the RAD52 S346X variant has been identified as reducing double-strand break (DSB) repair through the single strand annealing (SSA) pathway. The present findings may impact future cancer treatment and they suggests that inhibitors of RAD52 could be potentially used to reduce the risk of breast cancer in BRCA2 pathogenic variant carriers [9]. The inverse association between a breast cancer risk in carriers of BRCA2 mutation and the presence of a given SNP in another gene has been also observed for a polymorphism in ZNF365 (rs16917302), albeit not at a genome-wide level of significance. The association of this SNP was statistically significant in stage 1 of study but not in stage 2, although in combined analysis of stage 1 and stage 2, the ‘C’ allele was associated with reduced risk of developing breast cancer in BRCA2 pathogenic variants carriers [20]. Evidence of risk-modifying factors for breast cancer in carriers of BRCA2 mutation also indicates polymorphisms in other genes, such as ABL1 (rs3808814), CYP1B1-AS1 (rs184577), TFAP2A (rs9348512), LOC105376214 (rs865686), GMEB2 (rs311499) and ZNF365 (rs10995190) (Table 5).

Table 5 SNPs found to be associated with reduced breast cancer risk for BRCA2 pathogenic variants carriers
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Moreover, Minguillón et al. have investigated that CDK5RAP3 may influences breast cancer in BRCA1/2 mutation carriers by interacting with BRCA2 and supporting DNA repair. CDK5RAP3 downregulation leads to reduced genomic instability, DNA damage resistance and increased tumour aggressiveness, potentially accelerating cancer progression in BRCA1/2 mutation carriers. Additionally, it has been found that genetic variations in the CDK5RAP3 locus are associated with breast cancer risk in BRCA1/BRCA2 PV carriers, highlighting its role in cancer etiology [52].

Breast cancer in BRCA2 pathogenic variants carriers is primarily ER-positive [53]. This means that SNPs associated with ER-positive breast cancer in general population, which represent the majority of susceptibility variants identified through GWAS, are at most associated with higher risk of developing disease in individuals carrying mutations in BRCA2 gene [54]. Such an association with ER-positive tumours has been identified, among others, for: FGFR2 (rs2981582), TOX3/TNRC9 (rs3803662), LSP1 (rs3817198) and SLC4A7/NEK10 (rs4973768) (Table 3). There is also evidence that SNPs in RNA genes, such as LINC02698 (rs2186703) and LOC105373204 (rs55998524) are associated with lobular breast cancer for BRCA2 mutation carriers [55].

For BRCA2 PV carriers, only polymorphisms in FGFR2 (rs2981582) and TFAP2A (rs9348512) reached GWAS significance threshold (p-value < 5.0 × 10− 8).

Conclusions

This study presents a review of existing data on the impact of genetic modifiers on breast cancer risk among individuals carrying pathogenic variants in the BRCA1 and BRCA2 genes. GWAS have contributed significantly to the identification of breast cancer susceptibility variants in the general population. Importantly, research conducted by CIMBA recognizing some of these variants as modifiers of breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants. The importance of these studies has been constantly increasing over the years and a greater number of research efforts focused on investigating the role of genetic modifiers [31].

An extensive knowledge about breast cancer risk modifiers, including genetic modifiers, has several benefits. One of the key advantages is improved risk stratification, which helps differentiate individuals with a high or low risk of developing breast cancer [56]. This allows for more personalized risk assessments rather than a ‘one-size-fits-all’ approach. With better risk prediction, screening and surveillance strategies can also be tailored more effectively. Lower-risk individuals may avoid unnecessary procedures, while those at higher risk can undergo more intensive screening. Additionally, personalized prevention strategies can be developed, including lifestyle modifications or chemoprevention, based on an individual’s specific risk profile. Also refined risk estimates may be helpful for carriers in making decisions, especially when it came to determining the timing of prophylactic surgeries [57, 58]. Some of the genetic modifiers identified have been already integrated into existing breast cancer risk prediction models. Among the SNPs discussed in our review, three variants (TERT rs10069690, EMBP1 rs11249433, FGF10/MRPS30 rs10941679) are incorporated in PRS313 [59]. PRS313 is a well-validated polygenic risk score for breast cancer in the general population, covering 313 breast cancer-associated variants. Its association with breast cancer risk has been demonstrated in multiple studies and resulted in its inclusion in cancer prediction models such as BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm), Tyrer-Cuzick Model (IBIS Risk Evaluator) or Breast and Prostate Cancer Cohort Consortium (BPC3) Risk Model [59,60,61]. Additionally, PRS has been shown to result in absolute risk differences for the development of breast cancer in BRCA1/2 PV carriers. In a study by Barnes et al. [62] PRS313 was significantly correlated with breast cancer risk (HR = 1.31, 95% CI [1.27–1.36]) among BRCA2 PV carriers. Furthermore, the (ER)-negative PRS 313(which uses the same variants but with weights adapted to provide better prediction for ER-negative disease) was associated with breast cancer risk (HR = 1.29, 95% CI [1.25–1.33]) among BRCA1 PV carriers. However, the effect was smaller than in the general population. Another study indicated that the estimated lifetime breast cancer risk for BRCA1 and BRCA2 PV carriers increased with higher PRS313 scores, though the observed effect was smaller than in the general population or among carriers of PVs in ATM, CHEK2, and PALB2 [63]. Furthermore, PRS313 has demonstrated potential in refining contralateral breast cancer risk predictions for BRCA1/2 PV carriers. For BRCA1 heterozygotes, the (ER)-negative PRS313 showed the strongest association with contralateral breast cancer risk (HR = 1.12, 95% CI [1.06–1.18]), while for BRCA2 heterozygotes, the ER-positive PRS313 was more strongly associated with contralateral breast cancer risk (HR = 1.15, 95% CI [1.07–1.25]) [64]. Despite these findings support the utility of PRS313 in risk prediction, it is essential to recognize that PRS-based screening programs require validation in prospective, randomized clinical trials. Ongoing studies, including Wisdom (ClinicalTrials.gov identifier: NCT02620852) and eMERGE in the United States, MyPeBS (ClinicalTrials.gov identifier: NCT03672331) in Europe, and PERSPECTIVE I&I in Canada, are currently exploring the effectiveness of PRS in breast cancer screening. The outcomes of these trials will ultimately determine whether PRS can enhance the personalization of breast cancer screening programs [65].

Another significant benefit is the potential for targeted therapies. Understanding how genetic modifiers influence breast cancer risk may result in identification of new molecular pathways that may serve as therapeutic targets. This could lead to more effective treatments for BRCA1 and BRCA2 PV carriers. Furthermore, studying genetic modifiers enhances the overall understanding of tumour biology, shedding light on the complex interactions that drive cancer development in these individuals [66]. Finally, identifying genetic modifiers can have a meaningful impact on psychosocial and reproductive decision-making. More precise risk information enables individuals to make informed choices about family planning and preventive measures, reducing uncertainty and anxiety [67, 68]. Overall, these benefits contribute to a more personalized and effective approach to healthcare for BRCA1 and BRCA2 carriers.

Although genetic risk modifiers appear promising for improving risk prediction, personalized prevention, and targeted therapies, several challenges must be addressed before they can be effectively integrated into clinical practice [66]. One major difficulty is related to complexity of genetic interactions. Breast cancer risk is influenced by multiple genetic and environmental factors, with genetic modifiers often having small individual effects. This makes it difficult to point their exact contributions. Additionally, interactions between different genes further complicate risk prediction, as the effect of one modifier may depend on the presence of another [69, 70]. Another challenge is the need for large sample sizes. Since genetic modifiers often have subtle effects, detecting them requires extensive and diverse study populations. Recruiting enough BRCA1 and BRCA2 mutation carriers for statistically significant findings is difficult, as they represent only a small subset of breast cancer patients. This limitation can slow down research progress and complicate the ability to draw definitive conclusion. Variability across populations also poses a problem. Genetic risk modifiers may differ among ethnic and ancestral groups, meaning that findings from one population may not be applicable to others [66, 71, 72]. This highlights the need for studies with broad, diverse representation or large studies within specific populations to ensure that risk models are inclusive and accurate for all individuals. Environmental and lifestyle factors further complicate research on genetic modifiers. Factors such as diet, exercise, and hormonal determinants can modify breast cancer risk, making it difficult to isolate the effect of specific genetic modifiers. These variables need to be taken into account to draw accurate conclusions [73]. Another major obstacle is the limited functional understanding of genetic modifiers. Even when they are identified through genome-wide association studies (GWAS), their biological role in cancer development is often unclear. Without a deeper understanding, it is challenging to translate genetic findings into actionable insights that can improve risk assessment and treatment strategies [74, 75].

Finally, despite growing evidence that polygenic risk scores PRS and other common genetic variants may modulate breast cancer risk, integrating this information into risk prediction models for BRCA1/2 carriers is filled with challenges. The already high baseline risk in these individuals limits the relative impact of genetic modifiers, making it difficult to derive clinically meaningful stratification. Furthermore, the clinical utility of such refined risk estimates is not yet fully established. Current guidelines are primarily based on the presence of high-penetrance mutations, and the introduction of PRS-based stratification would require rigorous validation, standardization of scores, and clear demonstration of added predictive value. Additionally, ethical considerations, patient communication, and potential anxiety around more nuanced risk categories pose practical barriers.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

PV:

Pathogenic variant

SNP:

Single nucleotide polymorphism

CNV:

Copy number variation

GWAS:

Genome–wide association study

WES:

Whole exome sequencing

WGS:

Whole genome sequencing

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  1. Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland

    Roksana Dwornik & Katarzyna Białkowska

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Dwornik, R., Białkowska, K. Insights into genetic modifiers of breast cancer risk in carriers of BRCA1 and BRCA2 pathogenic variants. Hered Cancer Clin Pract 23, 15 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13053-025-00313-y

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Hereditary Cancer in Clinical Practice

ISSN: 1897-4287