Identification of Functional SNPs in BARD1 Gene and In Silico Analysis of Damaging SNPs: Based on Data Procured from dbSNP Database

Abstract

BackgroundThe BARD1 gene encodes for the BRCA1-associated RING domain (BARD1) protein. Germ line and somatic mutations in BARD1 are found in sporadic breast, ovarian and uterine cancers. There is a plethora of single nucleotide polymorphisms (SNPs) which may or may not be involved in the onset of female cancers. Hence, before planning a larger population study, it is advisable to sort out the possible functional SNPs. To accomplish this goal, data available in the dbSNP database and different computer programs can be used. To the best of our knowledge, until now there has been no such study on record for the BARD1 gene. Therefore, this study was undertaken to find the functional nsSNPs in BARD1.Result2.85% of all SNPs in the dbSNP database were present in the coding regions. SIFT predicted 11 out of 50 nsSNPs as not tolerable and PolyPhen assessed 27 out of 50 nsSNPs as damaging. FastSNP revealed that the rs58253676 SNP in the 3′ UTR may have splicing regulator and enhancer functions. In the 5′ UTR, rs17489363 and rs17426219 may alter the transcriptional binding site. The intronic region SNP rs67822872 may have a medium-high risk level. The protein structures 1JM7, 3C5R and 2NTE were predicted by PDBSum and shared 100% similarity with the BARD1 amino acid sequence. Among the predicted nsSNPs, rs4986841, rs111367604, rs13389423 and rs139785364 were identified as deleterious and damaging by the SIFT and PolyPhen programs. Additionally, I-Mutant showed a decrease in stability for these nsSNPs upon mutation. Finally, the ExPASy-PROSIT program revealed that the predicted deleterious mutations are contained in the ankyrin ring and BRCT domains.ConclusionUsing the available bioinformatics tools and the data present in the dbSNP database, the four nsSNPs, rs4986841, rs111367604, rs13389423 and rs139785364, were identified as deleterious, reducing the protein stability of BARD1. Hence, these SNPs can be used for the larger population-based studies of female cancers.

In silico SNP analysis of the breast cancer antigen NY-BR-1

“…The BRCA-1 gene for example and some of its interaction partners are associated with breast cancer. SNPs in these genes are not just involved in the onset of a disease but they can promote also disease progression and outcome [23, 24]. Here, we systematically analyzed SNPs in the NY-BR-1 gene to identify those SNPs which can modify the functional properties of the protein.…”

Multimodal approach to explore the pathogenicity of BARD1, ARG 658 CYS, and ILE 738 VAL mutants

“…Noting the role of BARD1 in genomic integrity, we decided to explore functional consequences of genetic alterations discovered in the BARD1 BRCT region. Two cancer predisposing mutations, Arg658Cys in Caucasian, African, Finnish population and Ile738Val in Polish and Belgian families have been detected (Thai et al 1998;Karppinen, Heikkinen, Rapakko & Winqvist 2004;Antoniou et al 2010;De Brakeleer et al 2010;Alshatwi, Hasan, Syed, Shafi & Grace 2012) but the molecular mechanism of how these mutations of BARD1 gene lead to breast cancer has not been explored. Further, in sporadic and BRCA1 associated breast cancers, expression of BARD1 is observed to be too low suggesting a significant role of BARD1 in breast carcinogenesis (Yoshikawa et al 2000;Ghimenti et al 2002).…”

Characterization ofLGALS3(galectin-3) as a player in DNA damage response

“…However, BARD1 tBRCT domain (located in its C-terminal) was also proven of functional relevance, depicted by cancer predisposing mutations affecting this domain. 19,20 The BARD1 tBRCT domain is also reported as an interaction domain, mediating protein-protein associations by specific phosphorylated motifs (e.g., pSer-X-X-Phe). 21 Curiously, the sequence Ser-Val-Phe-Pro-Phe-Glu-Ser (amino acids 188-194) found in the identified GAL3 fragment (Fig.…”