XRCC2 (x-ray repair cross-complementing gene-2) encodes a protein is which is a RAD51 paralog. XRCC2 involves in homologous recombination repair of DS DNA breaks [48]. Even though mutations in this gene are uncommon, it has increased risk of BC with family history [43]. Protein-truncating variant, one-base-pair deletion and p.R188H missense mutations were reported which may have increased BC risk. It was reported in a recent study that polymorphic site at XRCC1 is playing a double role in BC with anti tumor activity and promotion of metastasis [5].
However, XRCC2 mutation BC susceptibility requires further investigation [10].
2.8 ATR
ATR, also known as ataxia ATR encodes a protein that activates CHK1, TP53, and BRCA1 and RAD. Germline mutations in this gene confer increased risk of developing BC [36].
2.10 CDK1
Cyclin-dependent kinase 1 (CDK1) governs the G2/M transition of the cell cycle. CDK1 is important on DNA damage response and it phosphorylates BRCA1. Any functional change in CDK1 results in deficient DNA damage response signalling and DNA repair by HR.
CDK1 may interfere with DNA damage response and can increase the risk of tumour formation including BC [36].
Table 2: hereditary breast cancer moderate penetrance genes
Gene Location Function
PALB2 16p12.1 Binding partner and localizer of BRCA2 associated with DNA homologous recombination repair
ATM 11q22.3 Associated with DNA double-strand break repair and cell cycle progression
CHEK2 22q12.1 Associated with DNA double-strand break repair; also phosphorylatesBRCA1
BARDI 2q34-q35 DNA repair, apoptosis, RNA processing and cell cycle regulation
BRIP1 17q22–q24 Encodes protein serving as binding partner of BRCA1
MRE11, RAD50, NBS1 11q21, 5q31, 8q21.
3 Associated with DNA double-strand break repair
XRCC2 7q36.1 Homologous recombination repair of double-stranded DNA breaks
ATR 11q22.3 Activates CHK1, TP53, and BRCA1 and RAD.
CDK1 10q21.2 Governs the G2/M transition of the cell cycle.
3 Low penetrance genes
Genome-wide association studies (GWAS) led to the identification of many low penetrance genes/alleles with elevated BC risk [16]. Low penetrance alleles are often single nucleotide polymorphisms (SNPs) and they act in a combinational polygenic manner in an individual for the development of BC in an individual. At least 33-40 of complex SNPs interactions are needed to explain a threefold increased BC risk [15]. Some frequent Low penetrance genes/alleles are explained below.
3.2 ARLTS1
ARLTS1 (ADP-ribosylation factor-like tumour suppressor gene) is a tumour suppressor gene encodes GTP-binding proteins which are involved in multiple cell regulatory functions including apoptosis. Mutation in this low penetrance gene associated with familial melanoma and chronic lymphocytic leukaemia. A nonsense mutation in ARLTS1 leads to truncated protein which cannot bind GTP. A germline substitution of adenine for guanine is associated with increased risk of HBC regardless of the BRCA mutation status [38].
3.2 ABRAXAS
ABRAXAS is also known as (ABRA1, CCDC98, or FAM175A) codes a protein. This protein is an important component of the BRCA1 holoenzyme complex as it binds to BRCA1 BRCT motifs via its phosphorylated C-terminus. Because of the strong association with BRCA1, Abraxas could be cancer susceptibility gene and may play a role in HBOC [10].
3.3 MDM2
The protein encoded by MDM2 binds to p53 and inhibits its function in the absence of stress. MDM2 also has p53-independent determinal effect on on the repair of DS DNA. Polymorphism located in the promoter region 309 bp downstream from intron one results in a base change (T309G) has been associate with overexpression of MDM2. MDM2 has been shown to be overexpressive in multiple cancers. This polymorphism accelerates tumour formation and associated with early-onset BC [38].
3.4 PARP4
The protein encoded polymerase family member 4 (PARP4) genes add ADP-ribose to proteins. Recent studies have found that PARP4 is mutated in patients having thyroid and BC suggesting germline mutations in this gene can increase the risk of BC [1, 49].
3.5 CASP8
Chromosome 2q33–q34 is the genomic location of caspase 8 (CASP8). CASP8 is a cysteine protease involved in the initiation of apoptosis or programmed cell death in response to DNA damage [16]. Some SNPs in CASP8 was identified to confer a slightly increased risk of BC and consider as a BC lower penetrance susceptibility gene [10].
3.6 NF1
Ras/Raf/Erk signal transduction pathway is negatively regulated by Neurofibromin 1 (NF1). Mutations in this gene are associated with neurofibromatosis type 1 (NF1) and cancers including BC [36].
3.7 FGFR2
Fibroblast growth factor receptor 2 (FGFR2) gene located on chromosome 10q26 [16]. The FGFR2 rs2981582, rs2420946, and rs1219648 polymorphisms reported as modifiers of BC risk in nonBRCA1/2 carriers [36].
3.8 LSP1
Lymphocyte-specific protein 1 (LSP1) located on chromosome 11p15.5 [16]. This gene encodes an intracellular F-actin binding protein which has plays a role in the regulation of neutrophil motility and trans-endothelial migration. The LPS1 rs3817198 polymorphism has been reported to have a small increased risk of BC [36].
3.9 MAP3K1
Mitogen-activatedd protein kinase kinase kinase 1 E3 ubiquitin-protein ligase (MAP3K1) located on chromosome 5q11.2 [16]. The protein encoded by this gene is important in cell signalling, proliferation and apoptosis [50]. MAP3K1 rs889312 polymorphism reported being associated with a small increased risk of familial and early-onset BC [36].
3.10 TGFB1
Transforming growth factor β1 (TGFB1) gene mutations cause a disease condition called Camurati-Engelmann disease. The rs1982073 TGFB1polymorpysm has been reported to have slightly increased risk of developing PR-negative BC [36].
3.11 TOX3
TOX high mobility group box family member 3 (TOX3) gene located on chromosome 16q12 [50]. TOX3 encodes a protein involves in alteration of chromatin structure and act as predicted to act as a transcription factor [50]. Polymorphism rs3803662 TOX3 reported having an increased risk of developing BC [36].
3.12 VEGF
Major function of vascular endothelial growth factor (VEGF) is tumour angiogenesis. Genetic alterations in VEGF reported having functional influence of BC in BRCA mutation carriers [36].
3.13 TNRC9
TNRC9 is located on chromosome 16q and genetic variation in this gene associated with slightly increased the risk in developing BC [16].
3.14 H19
H19 gene is located on 11p and SNPs in this locus associated with slightly increased in the risk of developing BC [16].
3.15 ESR1
Estrogen receptor 1 (ESR1) is located on chromosome 6q25.1 and polymorphism rs2046210 in ESR1 has been associated with slightly increased risk of developing BC [50]
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