Table 1 discusses the genetic vulnerability to FBC, including genes with additional gene characteristics related to different malignancies, localisation, syndrome, function, therapy, and prevention. High penetrance genes increase BC susceptibility due to mutations that significantly increase the likelihood of developing the disease over an individual’s lifetime. These genes may lead to a lifetime risk of BC as high as 80% [18]. Moderate-penetrance genes like CHEK2, BRIP1, ABM, and PALB2 increase the likelihood of FBC by 20–50% throughout an individual’s life. High-penetrance genes in FBC are crucial for DNA repair and tumor suppression, increasing cancer risks when mutations occur. Moderate-penetrance genes have a lesser effect on risk and are more frequently mutated in the general population. Low-penetrance genes contribute to risk in a less obvious way, often requiring multiple variations to increase vulnerability. Understanding these differences is essential for genetic counselling and risk management in families with a history of BC. A range of genes, exhibiting high predisposition to intermediate and poor outcomes, have been linked to FBC (approximately 30%). Such instances are often observed in families with a high incidence of BC [19]. Notably, genes like BRCA1/2 are connected to FBC, contributing to around 5% of BC-related mutations and potentially accounting for 16–25% of FBC cases [20, 21]. Additionally, mutations in genes such as TP53, PTEN, STK11, and CDH1 are responsible for 5% of the risk associated with FBC and are linked to hereditary disorders. Low-sensitivity genes contribute to about 18% of the risk associated with FBC.

BRCA1 and BRCA2 are tumor suppressor genes that repair DNA and regulate cell growth. BC risk increases considerably with gene mutations via autosomal dominant inheritance. BRCA1, on chromosome 17q21, encodes a 220 kDa nuclear phosphoprotein with 1863 amino acids in 24 exons [21]. BRCA1 exons are divided into N-terminal RING fingerprint domain, C-terminal BRCT domain, each playing critical roles [22]. BRCA2, located on chromosome 13q12.3, encodes a 380 kDa protein with 27 distinct domains, including a transcriptional activation domain, a middle section with 8 BRC repeats binding to RAD51, a C-terminus DNA binding domain, nuclear localization signals, and a TR2 domain stabilizing RAD51-DNA interactions [23, 24]. BRCA1/BRCA2 gene mutations account for 16-25% of FBC cases and 5% of BC-related gene mutations [25, 21] with BRCA1-linked tumors lacking ER expression and BRCA2-linked tumors showing ER positivity [22]. Over 2000 mutations have been reported in BRCA1/BRCA2 genes, including deletions, insertions, and single nucleotide substitutions within coding or noncoding sequences [26]. The most common BRCA1 variations are 185delAG, 5382insC, and C61G [27]. The 185delAG mutation, a recurring genetic alteration in the Southern Indian population, accounts for 24.6% of the disease-causing variations [28]. Common BRCA2 mutations include 6174delT, 

10,204 A > T, 3036del4, and 6503delTT. In North-East Indian patients, 185DelAG, 1014DelGT, and 3889DelAG mutations in BRCA1 exons 2 and 11 caused protein truncation [29]. Another common mutation, 3889DelAG, interacts with BRCA2 protein and is more common in the Northeast [29, 30]. BRCA1 c.894delT, c.869delT, c.981–982delAT, c.1132delA, c.1252G > T, c.1953–1956delGAAA, c.5566 C > T, c.5533-5540delATTGGGCA, c.5154G > A, c.5215 + 2dupT, and in BRCA2, c.37G > T, c.262-263delCT, c.433dupG, c.439 C > T,

c.470–474delAGTCA, c.771–775delTCAAA, c.8377G > T, c.8584dupC, c.8687–8690delGTGC, c.10,150 C > T, c.7409dupT, c.7673–7674delAG, c.6547delG, c.7090G > T, c.3109 C > T are pathogenic or likely pathogenic variation reported in the Eastern Chinese population [31].

The BRCA2 gene mutations c.3482dup and c.8878 C > T have been linked to an increased risk of BC in southern Brazil [32]. The variants c.5470_5477del and c.5521del in the BRCA1 gene, as well as c.5167_5165del in the BRCA2 gene, have been seen in Chinese descent [33, 34].

TP53, also known as “the genome caretaker”, located on chromosome 17p13.1, encoding a 43.7 kDa phosphoprotein p53 with 393 amino acid residue [35]. The p53 polypeptide comprises various context-dependent functional domains, including the core DNA-binding domain, oligomerization domain, proline-rich domain, composite N-terminal transactivation domains (TAD1 and TAD2), and unstructured C-terminal domain (CTD) [36]. p53 mutations disrupt transcriptional processes, affecting DNA repair, senescence, apoptosis, autophagy, mitotic catastrophe, angiogenesis, and stress-induced phase transitions [37]. Notably, TP53 mutations most frequently manifest in exons 5–8 and occur in approximately 30% of BC cases. Reports suggest that around 5% of BC patients had mutations in CHEK2 or TP53 when they possess a positive family history and wild-type BRCA1/BRCA2 gene [38]. TP53’s proline-rich Pro72Leu/His/Arg (rs1042522) non-synonymous variation is remarkable. This exon 4 codon 72 polymorphism produces p53 proteins with different physicochemical and functional properties [39]. Recent studies show a strong relationship between the p53 codon 72 SNP with Indian vulnerability [40]. p.R337H Germline Variant among Women at Risk of HBC in a Public Health System of Midwest Brazil [41, 42],. According to the data, p. Arg181Cys is a founder pathogenic mutation that is most common among Arab Muslims in the Jerusalem and Hebron area [43].

CDH1, a tumor suppressor gene on chromosome 16q22.1, encodes a 120 kDa protein called E-cadherin [44]. It has 16 exons and 566 amino acids, with the C-Box motif in the N-terminal region influencing its connection with the APC/C complex. The cytoplasmic domain controls cellular functions like cell signalling, apoptosis, and invasion [45]. E-cadherin is a transmembrane protein essential for calcium-dependent cell-cell interaction, consisting of a transmembrane domain, a cytoplasmic domain, and five extracellular domains [44]. In the context of BC, E-cadherin’s normal activity serves as a deterrent against metastasis. However, CDH1 mutations are connected to an aggressive BC pattern characterized by lymphovascular invasion and axillary lymph node metastases, particularly within Invasive Lobular Carcinoma (ILC), which accounts for 5–15% of BC cases and is linked to CDH1 loss of function mutations [46, 47]. Individuals harbouring CDH1 mutations face a lifetime risk of 39% for developing BC, with a strong association to LBC. Among the Pashtun ethnic population of Khyber Pakhtunkhwa, the CDH1 (c.48 + 6 C > T, rs3743674) polymorphism has been identified as a contributing factor to an elevated risk of BC [48]. Furthermore, subsequent investigation unveiled the involvement of the CDH1 160 C/A (c.-124–161 C > A, rs16260) polymorphism in BC susceptibility [49].

Phosphatase and Tensin Homolog (PTEN), a BC-associated tumor suppressor gene on chromosome 10q23, is essential for survival and proliferation. It is 47.14 kDa and encodes 403 amino acids in 9 exons [50]. PTEN has N-terminal tyrosine phosphatase, C2-membrane binding, and PDZ-interaction motif domains. PTEN, a protein encoding phosphatidylinositol 3,4,5-triphosphate 3-phosphatase, is involved in the PI3K/AKT-mTOR signaling pathway, competing with PI3K and mitogen-activated protein kinase pathways to regulate cellular processes with lipid phosphatase activity [51]. Inactivation can occur through somatic mutations, gene deletions, and post-translational changes. Functional impairment from monoallelic or biallelic deletions and promoter methylation is common in PTEN. In 40–50% of BC, heterozygosity loss of PTEN gene occurs, with frameshift mutations being the main cause [52, 53].

In female Cowden Syndrome (CS) patients, the lifetime risk of BC ranges from 25 to 50%, and PTEN germline mutations are identified in 80–90% of CS families. Moreover, approximately 75% of female CS patients display various benign breast lesions such as fibroadenomas, cystic lesions, and ductal hyperplasia. The PTEN c.697 C > T (p. Arg233Ter, rs121909219) mutation introduces a premature stop codon in exon 7 of the gene encodes C2 domain and is linked to BC [54].

Serine/threonine protein kinase 11, regulates the cell cycle, promotes apoptosis, and inhibits tumor growth. On chromosome 19p13.3, STK11 has 9 coding and 1 non-coding exons. This 433-amino-acid, 50-kDa protein has an N-terminal kinase domain, a C-terminal regulatory domain [55]. STK11 mutation carriers had a 32–54% probability of BC, rising from 8% at 40 to 32% at age 60 [10]. For patients diagnosed with PJS, the lifetime probability of developing BC ranges from 24 to 54%, typically manifesting around the age of 39 [56]. In the general population, a missense variant p.S422G has been identified in the STK11 [57].

The Partner and Localizer of BRCA2 gene (PALB2), is located on chromosome 16p12.2. The PALB2 gene includes 13 exons, encoding a 1186 residues protein with 130 kDa size. PALB2 possess a core chromatin-associated motif, a coiled-coil domain at the N terminus that interacts with BRCA1, and a WD40 repeat domain at the c terminus that binds BRCA2[58]. Bi-allelic PALB2 germline mutations lead to Fanconi anaemia, whereas mono-allelic PALB2 germline mutations elevate the risk of breast, pancreatic, and ovarian cancer [59,60,61]. New investigations showed germline PALB2 mutations in BC families, indicating that PALB2 could serve as an FBC tumor suppressor [62, 63]. The presence of PALB2 mutations increases BC risk by 2–3 times, with carriers facing a cumulative risk of 35% within 0.6–2.7% of familial cases [64, 65].In Finland, a novel mutation (c.1592delT) led to a 4-fold increase in risk among individuals with or without a FH of the disease [63]. Various studies have indicated a modest risk associated with PALB2 mutations, displaying moderate penetrance in fewer than 1% of unselected BC cases and less than 3% in individuals with a FH of BC. Research from the UK, Finland, Italy, Spain, and Canada shows that PALB2 mutations are more prevalent in BC patients with a strong FH compared to unaffected controls [66]. Common SNPs within PALB2 exons, such as c.2586 + 58C > T (rs249954), c.2997-624G > C (rs447529), and c.1684 + 1597T > C (rs16940342), have a strong association with susceptibility to BC [67]. In addition, recent studies have identified specific mutations like c.3114-1G > A (rs886039619) and c.1057 A > G (c.1057 A > G) as frequent in FBC cases [68]. A missense mutation, c.1676 A > G (rs152451), was discovered in 31.1% of 122 multi-ethnic Malaysian BC patients, including 82 Chinese, 25 Malaysian, 12 Indian, and 3 miscellaneous cases [69]. Similarly, a study on the PALB2 gene within the North Indian population identified the mutation c.780delG in three patients with a high FBC risk, with a frequency of 1.5%. Furthermore, a novel mutation c.725delT was found in two patients with a frequency of 1% [70].

The tumor suppressor gene CHEK2 is located on chromosome 22q12.1 and it encodes a 65 kDa protein consisting of 543 amino acids. It plays a vital role in DNA repair, cell-cycle regulation, and the apoptotic response to DNA damage. CHEK2, N-terminal region contains a SQ/TQ cluster domain for phosphorylation in response to DNA damage, the fork head-associated protein interaction domain (FHA) for activation and rapid phosphorylation, and the C-terminal domain possesses serine/threonine kinase activity [71]. CHEK2 mutations are rare, individuals carrying truncating mutations are more susceptible to developing BC. The risk is correlated with FH, rising notably when carriers have affected first and second-degree relatives [72]. In carriers lacking affected relatives, the risk stands at approximately 20%, while carriers with affected relatives may see the risk climb to 44% [73]. The protein-truncating variant 1100delC (p. Thr367fs, rs555607708r) raises BC risk by two to three times in general risk [74], with 0.2–1.6% of Northern and Eastern Europeans harbouring this mutation, known as CHEK2 PV (Pathogenic variant) [75,76,77], while FBC cases were 4.8-fold [78].The 1100delC mutation has been specifically associated with ER-positive BC [74]. As a BC-sensitive factor, CHEK2 is interconnected with DNA damage, replication checkpoint feedback, higher-grade malignancies, and bilateral disease [75].Czech individuals with FBC have a recurrent CHEK2 gene variant, c.1009 − 118_1009-87delinsC, which disrupts pre-mRNA splicing and increases the risk of HBC [79].

BRCA1-interacting protein 1, a DEAH helicase family member, is located on human chromosome 17q23.2 and consists of 20 exons encoding a protein with 1249 amino acids of 141 kDa weight. Its interaction with BRCA1 is regulated by its N-terminal domain, playing a role in enhancing its DNA repair capabilities and tumor suppressor functions. Its C-terminal region has helicase activity and interacts with BRCA1 via BRCT repeats [80]. Deficiency in BRIP1 and constitutional truncating variants of BRIP1 that elevate BC risk have been connected with Fanconi’s anemia [81]. BRIP1 mutations contribute to about 1% of all BC [18]. The data indicates a significant correlation between two common polymorphisms, rs7220719 and rs11871753, and the risk of BC [82]. The Pro919Ser polymorphism (rs4986764), is strongly linked to BC susceptibility globally [83, 84]. However, a meta-analysis suggests that Asian women without BRCA1/2 mutations and those with a FH of BC may be less likely to develop this polymorphism [85].

Located on chromosome 11q23, the Ataxia-telangiectasia mutated (ATM) gene encodes a protein weighing 350 kDa, with 3056 amino acids, encoded by 66 exons on chromosome 11q23 [86]. ATM’s N-terminus contains multiple alpha helical repeat motifs and a critical region for interactions with proteins and DNA. It also has a FAT (FRAP) (FK506-binding protein 12-rapamcin-associated protein), ATM, TRAPP (Transformation/transcription domain-associated protein) domain and a FATC (FAT-C-terminal) domain on its C-terminal [87]. ATM serves as an intracellular sensor, activated in response to DNA double-strand breaks, and initiates phosphorylation of various downstream tumor suppressor proteins including BRCA1, TP53, CHK2, and CHK1 [88]. ATM genes are linked to two- to four-fold a higher lifetime risk of breast cancer [89, 90].Moslemi et al. discovered that ATM missense mutations increase BC risk by a factor of 2.8 to 3.04 [91], with the c.7271T > G (rs28904921) missense mutation demonstrating the strongest association with BC [92, 93]. while the ATM p. Asp1853Val (rs1801673) missense variant exhibits the weakest correlation [86].

Fibroblast growth factor receptor 2 (FGFR2) belongs to the family of tyrosine kinase receptors known as FGFR, which participate in various signalling pathways that impact cancer-related processes such as cell proliferation, apoptosis, and differentiation [94]. It is found on chromosome 10q26, encoding 22 exons, with 821 residues and molecular weight of 92.7 kDa. Overexpression of FGFR2 is linked to 10–15% of BC [95, 96]. Genome-wide association studies have also identified SNPs within the second intron of the FGFR2 gene as having a heightened association with an elevated risk of BC [97]. Further investigations have revealed that SNP within intron 2 of the FGFR2 gene can alter the binding of transcription factors Oct-1/Runx2 and C/EBPb, leading to changes in FGFR2 gene expression in breast tissue and cell lines [98]. The two intronic SNP variations of the FGFR2 gene are rs1219648 and rs2981582, both located in intron 2 have been associated with BC [99, 100]. Another study linked the SNP rs1219648 with an increased risk of SBC in the North Indian population [96]. Furthermore, amplification of the chromosomal region of FGFR1 (8p11-12) has been detected in approximately 10% of human BC, particularly those of the ER-positive subtype, and has been found to negatively impact overall survival [101].

Lymphocyte-specific protein 1 (LSP1) is a 339 amino acid F-actin binding protein found on chromosome 11p15.5, spans 20 exons, and has a molecular weight of 37.2 kDa [102]. It has an acidic N-terminal half and a basic C-terminal half. Its C-terminal half contains amino acid sequences homologous to the actin-binding domains of caldesmon and villin headpiece, making it a crucial F-actin binding protein [102]. LSP1 plays a role in regulating neutrophil motility, the adhesion of fibrinogen matrix protein, and trans-endothelial movement [103, 104]. LSP1 mutations has been identified in various conditions, including leukaemia, lymphomas, Hodgkin’s disease, and BC. The most prevalent alteration in the LSP1 gene is the polymorphism rs3817198T > C, which has been extensively associated with an increased risk of BC [105,106,107]. These LSP1 gene polymorphisms have the potential to modify protein expression, alter function, and impact downstream signalling pathways, ultimately influencing the risk of BC [16, 99, 108].

Mitogen activated protein kinase 1 is a serine/threonine kinase involved in the MAPK signalling cascade, located on chromosome 5q11.2. It has 20 exons, encoding 1512 residue protein of 196 kDa. It contains a plant homeodomain in its N-terminus and a phospho-kinase activity in its C-terminus. Numerous studies have demonstrated the involvement of MAP3K1 in processes such as cell survival, apoptosis, and cell motility across various normal and malignant cell types [109]. One specific polymorphism of MAP3K1, rs889312 (rs889312 A > C), has been associated with an elevated risk of distant metastatic development in BC. The MAP3K1 rs889312 polymorphism is linked to a higher risk of distant metastasis in BC with a mechanistic relationship identified in the Pakistani population, with the disease association strength being extensive in populations from East Asia, North Africa, and the Northern Hemisphere [110].

TGF (transforming growth factor beta) is a pleiotropic growth factor that regulates cell s