Next Article in Journal
Identification of Bradyrhizobium elkanii Genes Involved in Incompatibility with Vigna radiata
Next Article in Special Issue
NF-kappaB: Two Sides of the Same Coin
Previous Article in Journal / Special Issue
Context-Dependent Role of IKKβ in Cancer
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:

Dualistic Role of BARD1 in Cancer

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università Degli Studi di Napoli “Federico II”, 80131 Naples, Italy
CEINGE Biotecnologie Avanzate, 80131 Naples, Italy
IRCCS SDN, Istituto di Ricerca Diagnostica e Nucleare, 80143 Naples, Italy
Author to whom correspondence should be addressed.
Genes 2017, 8(12), 375;
Received: 24 October 2017 / Revised: 30 November 2017 / Accepted: 1 December 2017 / Published: 8 December 2017


BRCA1 Associated RING Domain 1 (BARD1) encodes a protein which interacts with the N-terminal region of BRCA1 in vivo and in vitro. The full length (FL) BARD1 mRNA includes 11 exons and encodes a protein comprising of six domains (N-terminal RING-finger domain, three Ankyrin repeats and two C-terminal BRCT domains) with different functions. Emerging data suggest that BARD1 can have both tumor-suppressor gene and oncogene functions in tumor initiation and progression. Indeed, whereas FL BARD1 protein acts as tumor-suppressor with and without BRCA1 interactions, aberrant splice variants of BARD1 have been detected in various cancers and have been shown to play an oncogenic role. Further evidence for a dualistic role came with the identification of BARD1 as a neuroblastoma predisposition gene in our genome wide association study which has demonstrated that single nucleotide polymorphisms in BARD1 can correlate with risk or can protect against cancer based on their association with the expression of FL and splice variants of BARD1. This review is an overview of how BARD1 functions in tumorigenesis with opposite effects in various types of cancer.

1. Introduction

In 1996, Wu et al. in effort to understand the function of BRCA1 they used a yeast two-hybrid screen to identify proteins that associate with it in vivo [1]. By this analysis the BRCA1-associated RING domain 1 (BARD1) protein was discovered as a binding partner of BRCA1. BARD1 protein is encoded by sequences on chromosome 2q35 and forms a functional heterodimer with BRCA1 through the binding of their RING-finger domains which functions as tumor-suppressor in breast and ovarian cancer [1,2,3,4]. The full length (FL) BARD1 mRNA includes 11 exons and encodes a protein comprising of one N-terminal RING-finger domain, three Ankyrin repeats (ANK) domains and two C-terminal BRCT domains (Figure 1). The recognizable protein motifs of BARD1 are well conserved in mouse [5,6], Xenopus laevis [7], Caenorhabditis elegans [8] and Arabidopsis thaliana [9], including the RING domain, the three tandem Ankyrin repeats and, to a lesser extent, the two BRCT domains. This complexity of structure indicates that BARD1 could have multiple functions.
Conditional inactivation of Bard1 in mice induces mammary carcinomas that are indistinguishable from carcinomas induced by conditional knock-out of Brca1, which establishes BARD1 itself as a tumor suppressor [10]. The knock-out of Brca1 and Brca2 genes in mice led to embryonic lethality. Similarly, homozygous disruption of Bard1 in mice results in lethality between embryonic days E7.5 and E8.5, at time when Bard1 but not Brca1 expression is maximal [5,11]. The phenotype of Bard1 knock-out mice demonstrated that Bard1 is essential for cell viability and maintenance of genome integrity and embryos lethality only after eight days of development could mean that Bard1 deficiency is deleterious to the cells. This hypothesis is supported by the finding that BARD1 mutations are associated with few cases of non-BRCA1/BRCA2-related sporadic breast and ovarian tumors and account for only a small fraction of cases of familial breast cancer overall [12,13,14,15,16]. Interesting to note, BRCA1 mutations do not immediately result in malignant phenotype but have cumulative effect that is possibly caused by incorrect stoichiometry with interacting proteins [17].
The BARD1-BRCA1 heterodimer has ubiquitin ligase activity that targets proteins involved in cell-cycle regulation, DNA repair, hormone signaling and modulating chromatin structure [18,19]. Several reports show that BARD1 has an additional BRCA1-independent tumor suppressor function in cancer that is antagonized by the expression of BARD1 isoforms. Briefly, the expression of FL BARD1 (tumor suppressor role) is required for genomic stability and cell cycle control; in cancer initiation and progression the expression of BARD1 isoforms (oncogenes) antagonize FL BARD1 functions and permit uncontrolled proliferation (Figure 1B) [5,20,21,22,23]. In the following review, we have focused on the genetic and molecular mechanisms of the dualistic role of BARD1 as oncogene and tumor-suppressor in cancer.

2. Rare and Common Cancer-Associated Genetic Variants of BARD1

2.1. Rare Predisposing Variants of BARD1 in Cancer

Mutations in the BRCA1 and BRCA2 genes are the most common causes of hereditary breast and ovarian cancer and are associated with a lifetime risk of breast cancer of 50–85% and of ovarian cancer of 15–40%. It is now apparent that mutations of several other genes, such as BARD1, PALB2 (Partner And Localizer Of BRCA2) and BRIP1 (BRCA1 Interacting Protein C-Terminal Helicase 1) [24], contribute to familial breast cancer. BARD1 mutations are expected to account for additional cases of non-BRCA1/2 inherited breast cancer and have been reported in non-BRCA mutated breast cancer families [25,26,27,28]. A recent work has suggested BARD1 as cancer-associated gene in ovarian cancer by a case-control association analysis between 1915 patients and Exome Sequencing Project (ESP, and Exome Aggregation Consortium (ExAC, controls [24]. The authors report a mutation frequency for BARD1 of 0.2% and Odd Ratio of 4.2 (95% confidence interval: 1.4–12.5). Similar results have been presented by Couch et al. from multigene panel-based clinical testing for pathogenic variants in inherited cancer genes among patients with breast cancer [29]. The case-control association analysis between 38,326 white patients with breast cancer and 26,911 ExAC controls demonstrated an association between pathogenic rare variants in BARD1 with a moderate risk value (Odd Ratio, 2.16; 95% confidence interval: 1.31–3.63) and a mutation frequency of 0.18% [29]. Thus, most of the published data are consistent with BARD1 involvement in breast and ovarian cancers susceptibility [12,13,14,15,16,25,26,27,28,29]. Indeed, BARD1 is now included on clinical gene panels for testing for susceptibility to these two tumors. However, no recurrent hotspot variant has been identified so far.
Beyond single nucleotide variants, other types of risk mutations have been found in BARD1 such as splicing mutations and large deletion. Interestingly, Ratajska et al. identified 16 BARD1 mutations in BRCA1/2-negative high-risk breast and/ovarian cancer patients from Poland [30]. Among these mutations, a splice mutation (c.1315-2A > G) resulted in exon 5 skipping and a silent change (c.1977A > G) which altered several exonic splicing enhancer motifs in exon 10 and resulted in a transcript lacking exons 2–9 [30]. In a recent study, three BARD1 mutations were identified that alter splicing leading to skipping of exons 5, 8 and 2–9, respectively [31].
The Table 1 shows the list of mutations (n = 79) defined as “Pathogenic” and “Likely Pathogenic” in ClinVar database ( Most of mutations are loss-function due to deletion, nonsense or frame shift mutations and are associated with susceptibility to breast cancer (Table 1 and Figure 2). Only one missense mutation is reported even if recent literature reports diverse potential pathogenic missense mutations in BARD1 [24,29]. Moreover, others and we have demonstrated that BARD1 is enriched in rare, potentially pathogenic, germline variants also in neuroblastoma patients [32,33]. Particularly, the nonsense variant (rs587781948; exon 2), included in ClinVar, has been found in two patients in these two different gene-sequence projects. Based on these observations a curated update of BARD1 mutations in ClinVar database is needed. We also expect that massive sequencing of BARD1 in breast, ovarian cancers, neuroblastoma and other tumors will increase the number of rare pathogenic missense mutations to be inserted into the ClinVar database as “Pathogenic”. However, these data strongly support the role of tumor-suppressor of BARD1 in different cancers.
Different copy number variants of BARD1 locus have been found associated with congenital conditions (hypospadias and congenital heart defects: coarctation of aorta and tetralogy of fallot) and developmental phenotypes (Table 1) [34]. Neuroblastoma, tetralogy of fallot and coarctation of aorta are related to tissues that origin from neural crest cells. Moreover, literature data report cases of patients with coexisting neuroblastoma and congenital heart defects [35]. In 2004 George et al. demonstrated that congenital heart defects are more common in neuroblastoma patients than in a control group of children with another type of cancer [36]. Another study has demonstrated that depleting frog embryos of BARD1 leads to defective developmental phenotypes (for instance: malformed neural tube and eye structures) [7]. Together, these evidences indicate that BARD1 might play a role in early organogenesis; however, additional studies are needed to demonstrate this hypothesis.
Although variants in protein-coding regions have received the most attention, numerous studies have noted the importance of non-coding variants in cancer. A sequencing of 20 complete genes, including noncoding and flanking sequences, in hereditary breast and ovarian cancer patients (n = 287) identified a single nucleotide variants in 5’ UTR (c.-53G > T; rs143914387) of BARD1 predicted to alter the mRNA structure [37]. Further complete gene sequencing or whole genome sequencing projects are warranted to investigate the contribution of rare non-coding variants of BARD1 in conferring cancer risk.

2.2. Common Predisposing Variants of BARD1 in Cancer

Many genome-wide association studies (GWAS), using high-density single nucleotide polymorphism (SNP)-based microarray technology, have been conducted in the commonest cancer types and have identified more than 4032 genetic associations (GWAS catalog, date: 21 August 2017), confirming that susceptibility to these diseases is polygenic. We have performed a large GWAS to define the genetic landscape of sporadic neuroblastoma predisposition and have identified common DNA alleles in different genes [38,39,40,41,42,43,44,45,46,47] that are associated significantly with neuroblastoma development. In that GWAS, one of the most significant and robustly replicated association signals that was enriched in the high-risk subset of neuroblastomas resided in the BARD1 locus [21] that is also the only neuroblastoma susceptibility gene validated in Afro-American [48], Chinese [49] and Spanish individuals [50]. We have demonstrated that, in BARD1 locus, SNPs associated with risk of neuroblastoma correlates with high expression of splice variants of BARD1 and SNPs protecting against neuroblastoma correlates with high expression of FL BARD1 [21]. Interestingly, one disease-associated variant (rs6435862) correlates with the expression of an oncogenetically activated isoform, BARD1β, which has growth-promoting effects in neuroblastoma models potentially through cooperation with the Aurora family of kinases [51]. Furthermore, by performing a fine mapping analysis of BARD1 locus, we have identified additionally functional polymorphisms associated with risk of neuroblastoma and over-expression of FL BARD1 [50]. These data strongly suggest that the dual role of BARD1 as oncogene or tumor-suppressor is due to the function of disease-associated variants. Together, these evidences highlight that the risk of neuroblastoma development may be estimated by a specific combination of BARD1 risk genotypes as suggested by the results of a published computational analysis of GWAS-identified neuroblastoma risk loci [52].
Recently, the SNP rs7585356 previously associated to neuroblastoma has been found also associated to nephroblastoma [53], which is the most frequent malignant renal tumor in children. Although the SNP rs7585356 located in 3’ UTR of BARD1 may have a role in BARD1 mRNA regulation, additional investigations are needed to validate this genetic association.
Candidate gene association studies have suggested that the low-frequency variant Cys557Ser (rs28997576) confers risk of single and multiple primary breast cancers in Icelandic [26] and South American [54] populations. However, independent studies failed to replicate that genetic association in Polish [55], multiethnic [56], Chinese [57], Australian [58] individuals. We also failed to validate that genetic association in a case series consisting of 540 high-risk neuroblastoma cases and 1142 controls [46] with European-American origins. These discordant results might be due to population substructure or gene modifiers affecting the role of BARD1 in cancer development.

2.3. Somatic Mutations of BARD1 in Cancer

Whereas common and rare hereditable variants of BARD1 have been associated with cancer risk, recent high-throughput sequencing studies have found no frequently acquired somatic mutations in tumor tissues. In accord to previous studies, our exome and deep sequencing of 82 clinically aggressive neuroblastomas detected only one somatic acquired mutation [32]. Interestingly, a large whole exome sequencing study on 500 metastatic cancers identified BARD1 among the genes somatically altered at low-frequency [59] and recently BARD1 has been included in the list of Cancer Gene Census in COSMIC database ( Here we have analyzed all somatic mutations of BARD1 deposited in COSMIC database by using the Cancer-specific High-throughput Annotation of Somatic Mutations (CHASM) [60] tool to distinguish passenger variation events from driver ones across a cohort of tumors and the Variant Effect Scoring Tool (VEST) [61] to identify variants that affect the molecular function of the protein and prioritize them on the basis of the likelihood of their involvement in human disease (Table 2). We confirm that even if pathogenic somatic mutations are relatively infrequent, BARD1 can be considered a cancer driver gene (CHASM gene score = 0.73; CHASM gene p-value = 0.0000004).

3. Biological Functions of BARD1 as Tumor Suppressor

Tumor suppressor functions of BRCA1 are thought to be mediated by the BARD1-BRCA1 heterodimer which is an E3 ubiquitin ligase implicated in DNA repair [18,19] and in other essential functions for maintaining genomic stability [62,63], as homologous recombination [64], centrosome duplication [62] and mitotic spindle assembly [65] (Figure 3). Specific functions of BARD1-BRCA1 heterodimer will not be dealt with in this paragraph. Although partner of this complex, FL BARD1 initiates or facilitates DNA repair pathways by controlling polyadenylation machinery in BRCA1-independent way through BARD1 binding with mRNA polyadenylation factor cleavage stimulation factor (CSTF1) [66,67].
BARD1 expression fluctuates in a cell-cycle dependent manner, with maximal expression levels occurring in mitosis [73]. In mitosis FL BARD1 stability is increased due to phosphorylation by cell-cycle dependent kinase complexes (cyclin A/E-CDK2 and cyclin B-CDK2) within regions required for ubiquitin ligase activity of BARD1-BRCA1 heterodimer [74]. Contrary, BRCA1 is mostly expressed during S-phase of cell-cycle [73]. We can speculate that the concomitant expression of BARD1 and BRCA1 in S-phase support the function of BARD1-BRCA1 heterodimer and FL BARD1 expression in mitosis supports additional BRCA1-independent functions.
BRCA1 and BARD1 have specific individual functions due to their interaction with various proteins and the dissociation of heterodimer might be regulated by post-translation protein modifications such as phosphorylation, ubiquitination or PARylation. Cancer-associated BRCA1-independent activities of BARD1 have been reported in various tumor cell lines (Figure 3). An access of monomer BARD1 over BRCA1 has been associated with BRCA1 mutations and with p53-mediated apoptosis. The link between BARD1 and apoptosis has been further highlighted by BARD1 co-immunoprecipitation with p53 in tissues exposed to genotoxic stress [70,71]. Particularly, the region of BARD1 binding with p53 involves ANK repeats and the region between ANK and BRCT domains in BARD1-C terminal fragment [72]. It is interesting to note that mutations or deletions in TP53 gene are frequent in cancer with BRCA1 mutations [75,76]. We can speculate that BRCA1 mutated tumors save BARD1 pro-apoptotic functions and additional TP53 mutations may enhance cancer development. Contrary deleterious BARD1 mutations are infrequent in cancer because the cells lose both DNA repair capabilities and pro-apoptotic function. BARD1 is also transcriptionally up-regulated in response to genotoxic stress and in brain after hypoxia suggesting that BARD1 is expressed specifically in tissues undergoing apoptosis [71].
BARD1 is involved in transcription factor NF-κB pathway. The binding of C-terminal fragment of BARD1 to the ANK repeats domain of BCL3, a NF-κB inhibitor in vitro, may affect the correct regulation of NF-κB in cancer and inflammatory and autoimmune diseases [68]. Emerging evidences report the interaction of BARD1 BRCT domain to poly(ADP-ribose) (PAR) and consequent recruitment of BARD1-BRCA1 complex to DNA repair after damage [69]. PAR pathway is particularly interesting because of the promising drugs act on inhibiting PAR polymerizing enzyme (PARP) are more efficient in cells BRCA1 mutated with saved BARD1 tumor suppressor function. Finally, a significant association found between over-expression of FL BARD1 and favorable outcome in colon cancer patients highlighted FL BARD1 function as prognostic factor in cancer [20].

4. Biological Functions of BARD1 as Oncogene

BARD1 is characterized by full length and diverse spliced isoforms (Figure 1). Down-regulation of FL BARD1 can have oncogenic effects [5,11,20,21] whereas BARD1 isoforms that lack RING or/and ANK domains are often up-regulated and associated with negative prognosis in breast [15], ovarian [15] endometrial [77] and lung [78] cancers. Several scientific evidences show that cancer-associated BARD1 isoforms antagonize the functions of FL BARD1 as tumor suppressor and act as a driving force for carcinogenesis.
BARD1β and BARD1δ isoforms were first identified in rat spermatocytes and in a highly tumorigenic and resistant to apoptosis rat ovarian cancer cell line NuTu-19 [70,79]. BARD1β is characterized by lack of exons 2 and 3 and encode to a protein lacking the RING finger and BRCA1 domain interaction. In breast and ovarian cancer an imbalance of FL BARD1 and BARD1β was observed with BARD1β dominant negative function. BARD1β scaffolds Aurora B and BRCA2 at the midbody during telophase and cytokinesis, antagonizing Aurora B ubiquitination and degradation by BARD1-BRCA1 E3 ubiquitin ligase [22]. BARD1β oncogenic driver of tumorigenesis is also supported by GWAS that identified BARD1 as new susceptibility locus in neuroblastoma as mentioned above [51]. BARD1β depletion in vitro caused genotype-specific inhibition of cell proliferation in neuroblastoma cells, whereas overexpression of BARD1β led to the transformation of non-malignant murine fibroblast [51,77].
BARD1δ is characterized by deletion of exons 2–6 that encode for the majority of the RING finger and the entirety of the ANK repeats, critical regions for the interaction with BRCA1 and p53; this isoform was detected in many gynecological cancers and in multiple processes of tumorigenesis [70,80,81]. In MCF-7 cells, BARD1δ does not stimulate apoptosis due to p53 deficiency [80]; however, its mitochondrial localization suggested a function in regulation of mitochondrial response to tumorigenic stress [82]. Interestingly, BARD1δ specifically binds to estrogen receptor alpha (ERα) antagonizing ERα-BARD1 binding and ERα degradation [83]. To note, BARD1δ dominant negative of FL BARD1 is temporally and spatially regulated by estrogen signaling in human invasive cytotrophoblasts cells of early pregnancy [81]. Recently, Maxim Pilyugin et al. described BARD1δ antagonizes chromosome and telomere protection function of BARD1-BRCA1 heterodimer by binding molecules that confer chromosome integrity [84]. It is likely that BARD1δ confers genomic instability and acquired oncogenic property in absence of cell cycle control, due to p53 deficiency and of chromosome integrity.
BARD1ω isoform contains only exons 6–11 encoding ANK repeats and BRCT domain. This isoform was found highly expressed in acute myeloid leukemia (AML) and in AML cell lines. In vitro BARD1ω overexpression induced multiple mitotic defects like aberrant chromosome alignment at the metaphase and anaphase state, abnormally increased size of nucleus and apoptosis inhibition. These scientific evidences highlight oncogenic proprieties of BARD1ω [85].

5. Summary and Future Perspectives

In this review, we summarized the genetic and molecular mechanisms associated to a dualistic role of BARD1 in cancer initiation: tumor suppressor and oncogene. BARD1 shows relatively low frequent mutations in cancer and, even if rare, BARD1 mutations seem to drive malignant transformation. The reduced expression of FL BARD1 due to somatic mutations or predisposition gene silencing variants may be considered the first hit of BARD1 tumor suppressor function. Instead, FL BARD1 loss-of function consequently to aberrant splicing and gain of dominant negative functions is associated with its proto-oncogenic role. Indeed, cancer associated BARD1 isoforms antagonize the functions of FL BARD1 as tumor suppressor and lead to genetic instability, loss of DNA repair and cell cycle control functions and permits uncontrolled proliferation. This antagonist effect is also supported from a more recently published research article that suggests that specific microRNAs, in healthy tissues, maintain an equilibrium of FL BARD1 and isoforms in favor of FL BARD1 instead, in cancer cells, create a disequilibrium in favor of BARD1 isoforms upon epigenetic activation of non-coding BARD1 isoform BARD1 9’L [23].
In ClinVar database, beyond deletion, nonsense or frame shift mutations, only one missense mutation of BARD1 is reported as “Pathogenic” even if recent literature demonstrates the association of common and rare point mutations with cancer initiation [29,86]. Thus, further functional investigations of non-coding and coding disease-associated variants are needed in order to verify their role in tumorigenesis and drug response.
BARD1 might also play a role in early organogenesis and in diseases related to tissues that origin from neural crest cells. In light of these evidences additional studies to explore BARD1 function in cancer and in developmental disorders should be considered in the next future.

BARD1 as Possible Biomarker and Therapeutic Possibilities

BARD1β has been identified as an oncogenic driver of high-risk neuroblastoma tumorigenesis and a stabilizer of Aurora family of kinases. This strongly supports the development of potential therapeutic strategy with Aurora kinase inhibitors for clinically aggressive neuroblastoma. Moreover, the switching from FL BARD1 to BARD1β permits the deregulated turnover of the Aurora kinases. Thus, Aurora and BARD1β expression levels might be predictive biomarkers for response to Aurora inhibitors.
Protein PARylation functions as a signal to recruit DNA damage repair proteins like the BARD1-BRCA1 complex to repair Double Strand Breaks (DSBs). BARD1 BRCTs bind ADP-ribose, the basic unit of PAR, at DNA damage sites which mediates the rapid recruitment of BRCA1. PARP inhibition directly suppresses the fast recruitment of the BARD1-BRCA1 heterodimer to DNA damage sites and impairs DNA repair. PARP inhibitors (PARPi) selectively kill BRCA1-deficient cells and several PARPi are currently in breast cancer clinical trials. However, the mechanism underlying the sensitivity of the tumor cells bearing BRCA1 mutations that abolish the interaction between BRCA1 and BARD1 to PARPi is not clear [87]. Ovarian and breast cancer patients who harbor BRCA1 mutations develop resistance to both PARPi and platinum therapy [88,89]. Secondary mutations in BRCA genes as well as gene methylation status for BRCA1, BRCA2 and other genes that control homologous recombination have been examined in patients’ biopsies as potential resistance mechanisms. One way to overcome clinical resistance is to investigate as the expression of FL or isoform BARD1 could contribute to the success or failure of PARPi therapy. A recent paper has demonstrated that BARD1β sensitizes colon cancer cells to poly PARP-1 inhibition even in a FL BARD1 background, thus suggesting that BARD1β may serve as a future biomarker to assess suitability of colon cancers for homologous recombination targeting with PARPi in treatment of advanced colon cancer [90]. In the future, it will be interesting to evaluate the efficacy of PARPi in patients with loss-of-function mutations of BARD1 that are relatively frequent (Table 1).
The early detection of cancer is the most important factor contributing to the total eradication of cancer. The over-expression of BARD1 isoforms is strongly correlated with tumor progression, specifically in non-small-cell lung cancer (NSCLC) [20,51,78]. Based on these evidences Irminger-Finger et al. have developed a blood test for the early detection and diagnosis of lung cancer based on capturing autoimmune antibodies against BARD1 antigens [91]. Additional studies are needed to verify the efficacy of this test in detection of lung cancer and it will be very interesting to extend this experimentation to other cancers such as neuroblastoma, ovarian and breast cancer.


This study was supported by grants from Associazione Italiana per la Ricerca sul Cancro (Grant No. 19255 to M.C.); Ministero della Salute (GR-2011-02348722 to M.C. and D.F.), Fondazione Italiana per la Lotta al Neuroblastoma (to M.C.); Associazione Oncologia Pediatrica e Neuroblastoma (to M.C.) and Fondazione Umberto Veronesi (to F.C.).

Conflicts of Interest

The authors declare no conflicts of interest.


  1. Wu, L.C.; Wang, Z.W.; Tsan, J.T.; Spillman, M.A.; Phung, A.; Xu, X.L.; Yang, M.C.; Hwang, L.Y.; Bowcock, A.M.; Baer, R. Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat. Genet. 1996, 14, 430–440. [Google Scholar] [CrossRef] [PubMed]
  2. Brzovic, P.S.; Meza, J.E.; King, M.C.; Klevit, R.E. BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein-protein interactions. J. Biol. Chem. 2001, 276, 41399–41406. [Google Scholar] [CrossRef] [PubMed]
  3. Irminger-Finger, I.; Ratajska, M.; Pilyugin, M. New concepts on BARD1: Regulator of BRCA pathways and beyond. Int. J. Biochem. Cell Biol. 2016, 72, 1–17. [Google Scholar] [CrossRef] [PubMed]
  4. Irminger-Finger, I.; Jefford, C.E. Is there more to BARD1 than BRCA1? Nat. Rev. Cancer 2006, 6, 382–391. [Google Scholar] [CrossRef] [PubMed]
  5. Irminger-Finger, I.; Soriano, J.V.; Vaudan, G.; Montesano, R.; Sappino, A.P. In Vitro repression of Brca1-associated RING domain gene, Bard1, induces phenotypic changes in mammary epithelial cells. J. Cell Biol. 1998, 143, 1329–1339. [Google Scholar] [CrossRef] [PubMed]
  6. Ayi, T.C.; Tsan, J.T.; Hwang, L.Y.; Bowcock, A.M.; Baer, R. Conservation of function and primary structure in the BRCA1-associated RING domain (BARD1) protein. Oncogene 1998, 17, 2143–2148. [Google Scholar] [CrossRef] [PubMed]
  7. Joukov, V.; Chen, J.; Fox, E.A.; Green, J.B.; Livingston, D.M. Functional communication between endogenous BRCA1 and its partner, BARD1, during Xenopus laevis development. Proc. Natl. Acad. Sci. USA 2001, 98, 12078–12083. [Google Scholar] [CrossRef] [PubMed]
  8. Boulton, S.J.; Martin, J.S.; Polanowska, J.; Hill, D.E.; Gartner, A.; Vidal, M. BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans. Curr. Biol. 2004, 14, 33–39. [Google Scholar] [CrossRef] [PubMed]
  9. Lafarge, S.; Montane, M.H. Characterization of Arabidopsis thaliana ortholog of the human breast cancer susceptibility gene 1: AtBRCA1, strongly induced by gamma rays. Nucleic Acids Res. 2003, 31, 1148–1155. [Google Scholar] [CrossRef] [PubMed]
  10. Shakya, R.; Szabolcs, M.; McCarthy, E.; Ospina, E.; Basso, K.; Nandula, S.; Murty, V.; Baer, R.; Ludwig, T. The basal-like mammary carcinomas induced by Brca1 or Bard1 inactivation implicate the BRCA1/BARD1 heterodimer in tumor suppression. Proc. Natl. Acad. Sci. USA 2008, 105, 7040–7045. [Google Scholar] [CrossRef] [PubMed]
  11. McCarthy, E.E.; Celebi, J.T.; Baer, R.; Ludwig, T. Loss of Bard1, the heterodimeric partner of the Brca1 tumor suppressor, results in early embryonic lethality and chromosomal instability. Mol. Cell. Biol. 2003, 23, 5056–5063. [Google Scholar] [CrossRef] [PubMed]
  12. Ghimenti, C.; Sensi, E.; Presciuttini, S.; Brunetti, I.M.; Conte, P.; Bevilacqua, G.; Caligo, M.A. Germline mutations of the BRCA1-associated RING domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosomes Cancer 2002, 33, 235–242. [Google Scholar] [CrossRef] [PubMed]
  13. Ishitobi, M.; Miyoshi, Y.; Hasegawa, S.; Egawa, C.; Tamaki, Y.; Monden, M.; Noguchi, S. Mutational analysis of BARD1 in familial breast cancer patients in Japan. Cancer Lett. 2003, 200, 1–7. [Google Scholar] [CrossRef]
  14. Karppinen, S.M.; Heikkinen, K.; Rapakko, K.; Winqvist, R. Mutation screening of the BARD1 gene: Evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. J. Med. Genet. 2004, 41, e114. [Google Scholar] [CrossRef] [PubMed]
  15. Wu, J.Y.; Vlastos, A.T.; Pelte, M.F.; Caligo, M.A.; Bianco, A.; Krause, K.H.; Laurent, G.J.; Irminger-Finger, I. Aberrant expression of BARD1 in breast and ovarian cancers with poor prognosis. Int. J. Cancer 2006, 118, 1215–1226. [Google Scholar] [CrossRef] [PubMed]
  16. Irminger-Finger, I. BARD1, a possible biomarker for breast and ovarian cancer. Gynecol. Oncol. 2010, 117, 211–215. [Google Scholar] [CrossRef] [PubMed]
  17. Deng, C.X. BRCA1: Cell cycle checkpoint, genetic instability, DNA damage response and cancer evolution. Nucleic Acids Res. 2006, 34, 1416–1426. [Google Scholar] [CrossRef] [PubMed]
  18. Hashizume, R.; Fukuda, M.; Maeda, I.; Nishikawa, H.; Oyake, D.; Yabuki, Y.; Ogata, H.; Ohta, T. The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J. Biol. Chem. 2001, 276, 14537–14540. [Google Scholar] [CrossRef] [PubMed]
  19. Baer, R.; Ludwig, T. The BRCA1/BARD1 heterodimer, a tumor suppressor complex with ubiquitin E3 ligase activity. Curr. Opin. Genet. Dev. 2002, 12, 86–91. [Google Scholar] [CrossRef]
  20. Sporn, J.C.; Hothorn, T.; Jung, B. BARD1 expression predicts outcome in colon cancer. Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res. 2011, 17, 5451–5462. [Google Scholar] [CrossRef] [PubMed]
  21. Capasso, M.; Diskin, S.J.; Totaro, F.; Longo, L.; De Mariano, M.; Russo, R.; Cimmino, F.; Hakonarson, H.; Tonini, G.P.; Devoto, M.; et al. Replication of GWAS-identified neuroblastoma risk loci strengthens the role of BARD1 and affirms the cumulative effect of genetic variations on disease susceptibility. Carcinogenesis 2013, 34, 605–611. [Google Scholar] [CrossRef] [PubMed]
  22. Ryser, S.; Dizin, E.; Jefford, C.E.; Delaval, B.; Gagos, S.; Christodoulidou, A.; Krause, K.H.; Birnbaum, D.; Irminger-Finger, I. Distinct roles of BARD1 isoforms in mitosis: Full-Length BARD1 mediates Aurora B degradation, cancer-associated BARD1β scaffolds Aurora B and BRCA2. Cancer Res. 2009, 69, 1125–1134. [Google Scholar] [CrossRef] [PubMed]
  23. Pilyugin, M.; Irminger-Finger, I. Long non-coding RNA and microRNAs might act in regulating the expression of BARD1 mRNAs. Int. J. Biochem. Cell Biol. 2014, 54, 356–367. [Google Scholar] [CrossRef] [PubMed]
  24. Norquist, B.M.; Harrell, M.I.; Brady, M.F.; Walsh, T.; Lee, M.K.; Gulsuner, S.; Bernards, S.S.; Casadei, S.; Yi, Q.; Burger, R.A.; et al. Inherited Mutations in Women With Ovarian Carcinoma. JAMA Oncol. 2016, 2, 482–490. [Google Scholar] [CrossRef] [PubMed]
  25. Thai, T.H.; Du, F.; Tsan, J.T.; Jin, Y.; Phung, A.; Spillman, M.A.; Massa, H.F.; Muller, C.Y.; Ashfaq, R.; Mathis, J.M.; et al. Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum. Mol. Genet. 1998, 7, 195–202. [Google Scholar] [CrossRef] [PubMed]
  26. Stacey, S.N.; Sulem, P.; Johannsson, O.T.; Helgason, A.; Gudmundsson, J.; Kostic, J.P.; Kristjansson, K.; Jonsdottir, T.; Sigurdsson, H.; Hrafnkelsson, J.; et al. The BARD1 Cys557Ser variant and breast cancer risk in Iceland. PLoS Med. 2006, 3, e217. [Google Scholar] [CrossRef] [PubMed][Green Version]
  27. Guenard, F.; Labrie, Y.; Ouellette, G.; Beauparlant, C.J.; Durocher, F.; BRCAs, I. Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian families with high risk of breast cancer. J. Hum. Genet. 2009, 54, 152–161. [Google Scholar] [CrossRef] [PubMed]
  28. De Brakeleer, S.; De Greve, J.; Loris, R.; Janin, N.; Lissens, W.; Sermijn, E.; Teugels, E. Cancer predisposing missense and protein truncating BARD1 mutations in non-BRCA1 or BRCA2 breast cancer families. Hum. Mutat. 2010, 31, E1175–E1185. [Google Scholar] [CrossRef] [PubMed]
  29. Couch, F.J.; Shimelis, H.; Hu, C.; Hart, S.N.; Polley, E.C.; Na, J.; Hallberg, E.; Moore, R.; Thomas, A.; Lilyquist, J.; et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 2017, 3, 1190–1196. [Google Scholar] [CrossRef] [PubMed]
  30. Ratajska, M.; Antoszewska, E.; Piskorz, A.; Brozek, I.; Borg, A.; Kusmierek, H.; Biernat, W.; Limon, J. Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res. Treat. 2012, 131, 89–97. [Google Scholar] [CrossRef] [PubMed]
  31. Ratajska, M.; Matusiak, M.; Kuzniacka, A.; Wasag, B.; Brozek, I.; Biernat, W.; Koczkowska, M.; Debniak, J.; Sniadecki, M.; Kozlowski, P.; et al. Cancer predisposing BARD1 mutations affect exon skipping and are associated with overexpression of specific BARD1 isoforms. Oncol. Rep. 2015, 34, 2609–2617. [Google Scholar] [CrossRef] [PubMed]
  32. Lasorsa, V.A.; Formicola, D.; Pignataro, P.; Cimmino, F.; Calabrese, F.M.; Mora, J.; Esposito, M.R.; Pantile, M.; Zanon, C.; De Mariano, M.; et al. Exome and deep sequencing of clinically aggressive neuroblastoma reveal somatic mutations that affect key pathways involved in cancer progression. Oncotarget 2016, 7, 21840–21852. [Google Scholar] [CrossRef] [PubMed]
  33. Pugh, T.J.; Morozova, O.; Attiyeh, E.F.; Asgharzadeh, S.; Wei, J.S.; Auclair, D.; Carter, S.L.; Cibulskis, K.; Hanna, M.; Kiezun, A.; et al. The genetic landscape of high-risk neuroblastoma. Nat. Genet. 2013, 45, 279–284. [Google Scholar] [CrossRef] [PubMed]
  34. Silversides, C.K.; Lionel, A.C.; Costain, G.; Merico, D.; Migita, O.; Liu, B.; Yuen, T.; Rickaby, J.; Thiruvahindrapuram, B.; Marshall, C.R.; et al. Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways. PLoS Genet. 2012, 8, e1002843. [Google Scholar] [CrossRef] [PubMed]
  35. Faingold, R.; Babyn, P.S.; Yoo, S.J.; Dipchand, A.I.; Weitzman, S. Neuroblastoma with atypical metastases to cardiac and skeletal muscles: MRI features. Pediatr. Radiol. 2003, 33, 584–586. [Google Scholar] [CrossRef] [PubMed]
  36. George, R.E.; Lipshultz, S.E.; Lipsitz, S.R.; Colan, S.D.; Diller, L. Association between congenital cardiovascular malformations and neuroblastoma. J. Pediatr. 2004, 144, 444–448. [Google Scholar] [CrossRef] [PubMed]
  37. Caminsky, N.G.; Mucaki, E.J.; Perri, A.M.; Lu, R.; Knoll, J.H.; Rogan, P.K. Prioritizing variants in complete hereditary breast and ovarian cancer genes in patients lacking known BRCA mutations. Hum. Mutat. 2016, 37, 640–652. [Google Scholar] [CrossRef] [PubMed]
  38. McDaniel, L.D.; Conkrite, K.L.; Chang, X.; Capasso, M.; Vaksman, Z.; Oldridge, D.A.; Zachariou, A.; Horn, M.; Diamond, M.; Hou, C.; et al. Common variants upstream of MLF1 at 3q25 and within CPZ at 4p16 associated with neuroblastoma. PLoS Genet. 2017, 13, e1006787. [Google Scholar] [CrossRef] [PubMed]
  39. Capasso, M.; McDaniel, L.D.; Cimmino, F.; Cirino, A.; Formicola, D.; Russell, M.R.; Raman, P.; Cole, K.A.; Diskin, S.J. The functional variant rs34330 of CDKN1B is associated with risk of neuroblastoma. J. Cell. Mol. Med. 2017, 21, 3224–3230. [Google Scholar] [CrossRef] [PubMed]
  40. Oldridge, D.A.; Wood, A.C.; Weichert-Leahey, N.; Crimmins, I.; Sussman, R.; Winter, C.; McDaniel, L.D.; Diamond, M.; Hart, L.S.; Zhu, S.; et al. Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism. Nature 2015, 528, 418–421. [Google Scholar] [CrossRef] [PubMed]
  41. Capasso, M.; Diskin, S.; Cimmino, F.; Acierno, G.; Totaro, F.; Petrosino, G.; Pezone, L.; Diamond, M.; McDaniel, L.; Hakonarson, H.; et al. Common genetic variants in NEFL influence gene expression and neuroblastoma risk. Cancer Res. 2014, 74, 6913–6924. [Google Scholar] [CrossRef] [PubMed]
  42. Diskin, S.J.; Capasso, M.; Diamond, M.; Oldridge, D.A.; Conkrite, K.; Bosse, K.R.; Russell, M.R.; Iolascon, A.; Hakonarson, H.; Devoto, M.; et al. Rare variants in TP53 and susceptibility to neuroblastoma. J. Natl. Cancer Inst. 2014, 106. [Google Scholar] [CrossRef] [PubMed]
  43. Diskin, S.J.; Capasso, M.; Schnepp, R.W.; Cole, K.A.; Attiyeh, E.F.; Hou, C.; Diamond, M.; Carpenter, E.L.; Winter, C.; Lee, H.; et al. Common variation at 6q16 within HACE1 and LIN28B influences susceptibility to neuroblastoma. Nat. Genet. 2012, 44, 1126–1130. [Google Scholar] [CrossRef] [PubMed]
  44. Nguyen le, B.; Diskin, S.J.; Capasso, M.; Wang, K.; Diamond, M.A.; Glessner, J.; Kim, C.; Attiyeh, E.F.; Mosse, Y.P.; Cole, K.; et al. Phenotype restricted genome-wide association study using a gene-centric approach identifies three low-risk neuroblastoma susceptibility Loci. PLoS Genet. 2011, 7, e1002026. [Google Scholar] [CrossRef] [PubMed]
  45. Wang, K.; Diskin, S.J.; Zhang, H.; Attiyeh, E.F.; Winter, C.; Hou, C.; Schnepp, R.W.; Diamond, M.; Bosse, K.; Mayes, P.A.; et al. Integrative genomics identifies LMO1 as a neuroblastoma oncogene. Nature 2011, 469, 216–220. [Google Scholar] [CrossRef] [PubMed]
  46. Capasso, M.; Devoto, M.; Hou, C.; Asgharzadeh, S.; Glessner, J.T.; Attiyeh, E.F.; Mosse, Y.P.; Kim, C.; Diskin, S.J.; Cole, K.A.; et al. Common variations in BARD1 influence susceptibility to high-risk neuroblastoma. Nat. Genet. 2009, 41, 718–723. [Google Scholar] [CrossRef] [PubMed]
  47. Maris, J.M.; Mosse, Y.P.; Bradfield, J.P.; Hou, C.; Monni, S.; Scott, R.H.; Asgharzadeh, S.; Attiyeh, E.F.; Diskin, S.J.; Laudenslager, M.; et al. Chromosome 6p22 locus associated with clinically aggressive neuroblastoma. N. Engl. J. Med. 2008, 358, 2585–2593. [Google Scholar] [CrossRef] [PubMed]
  48. Latorre, V.; Diskin, S.J.; Diamond, M.A.; Zhang, H.; Hakonarson, H.; Maris, J.M.; Devoto, M. Replication of neuroblastoma SNP association at the BARD1 locus in African-Americans. Cancer Epidemiol. Biomark. Prev. 2012, 21, 658–663. [Google Scholar] [CrossRef] [PubMed]
  49. Zhang, R.; Zou, Y.; Zhu, J.; Zeng, X.; Yang, T.; Wang, F.; He, J.; Xia, H. The Association between GWAS-identified BARD1 Gene SNPs and Neuroblastoma Susceptibility in a Southern Chinese Population. Int. J. Med. Sci. 2016, 13, 133–138. [Google Scholar] [CrossRef] [PubMed]
  50. Cimmino, F. BARD1 locus of neuroblastoma susceptibility; Università di Napoli Federico II: Naples, Italy, 2017. [Google Scholar]
  51. Bosse, K.R.; Diskin, S.J.; Cole, K.A.; Wood, A.C.; Schnepp, R.W.; Norris, G.; Nguyen, L.B.; Jagannathan, J.; Laquaglia, M.; Winter, C.; et al. Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity. Cancer Res. 2012, 72, 2068–2078. [Google Scholar] [CrossRef] [PubMed]
  52. Capasso, M.; Calabrese, F.M.; Iolascon, A.; Mellerup, E. Combinations of genetic data in a study of neuroblastoma risk genotypes. Cancer Genet. 2014, 207, 94–97. [Google Scholar] [CrossRef] [PubMed]
  53. Fu, W.; Zhu, J.; Xiong, S.W.; Jia, W.; Zhao, Z.; Zhu, S.B.; Hu, J.H.; Wang, F.H.; Xia, H.; He, J.; et al. BARD1 gene polymorphisms confer nephroblastoma susceptibility. EBioMedicine 2017, 16, 101–105. [Google Scholar] [CrossRef] [PubMed]
  54. Gonzalez-Hormazabal, P.; Reyes, J.M.; Blanco, R.; Bravo, T.; Carrera, I.; Peralta, O.; Gomez, F.; Waugh, E.; Margarit, S.; Ibanez, G.; et al. The BARD1 Cys557Ser variant and risk of familial breast cancer in a South-American population. Mol. Biol. Rep. 2012, 39, 8091–8098. [Google Scholar] [CrossRef] [PubMed]
  55. Jakubowska, A.; Cybulski, C.; Szymanska, A.; Huzarski, T.; Byrski, T.; Gronwald, J.; Debniak, T.; Gorski, B.; Kowalska, E.; Narod, S.A.; et al. BARD1 and breast cancer in Poland. Breast Cancer Res. Treat. 2008, 107, 119–122. [Google Scholar] [CrossRef] [PubMed]
  56. Spurdle, A.B.; Marquart, L.; McGuffog, L.; Healey, S.; Sinilnikova, O.; Wan, F.; Chen, X.; Beesley, J.; Singer, C.F.; Dressler, A.C.; et al. Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers. Cancer Epidemiol. Biomark. Prev. 2011, 20, 1032–1038. [Google Scholar] [CrossRef] [PubMed][Green Version]
  57. Ding, D.P.; Zhang, Y.; Ma, W.L.; He, X.F.; Wang, W.; Yu, H.L.; Guo, Y.B.; Zheng, W.L. Lack of association between BARD1 Cys557Ser variant and breast cancer risk: A meta-analysis of 11,870 cases and 7687 controls. J. Cancer Res. Clin. Oncol. 2011, 137, 1463–1468. [Google Scholar] [CrossRef] [PubMed]
  58. Johnatty, S.E.; Beesley, J.; Chen, X.; Hopper, J.L.; Southey, M.C.; Giles, G.G.; Goldgar, D.E.; Chenevix-Trench, G.; Spurdle, A.B. The BARD1 Cys557Ser polymorphism and breast cancer risk: An Australian case-control and family analysis. Breast Cancer Res. Treat. 2009, 115, 145–150. [Google Scholar] [CrossRef] [PubMed]
  59. Robinson, D.R.; Wu, Y.M.; Lonigro, R.J.; Vats, P.; Cobain, E.; Everett, J.; Cao, X.; Rabban, E.; Kumar-Sinha, C.; Raymond, V.; et al. Integrative clinical genomics of metastatic cancer. Nature 2017, 548, 297–303. [Google Scholar] [CrossRef] [PubMed]
  60. Carter, H.; Chen, S.; Isik, L.; Tyekucheva, S.; Velculescu, V.E.; Kinzler, K.W.; Vogelstein, B.; Karchin, R. Cancer-specific high-throughput annotation of somatic mutations: Computational prediction of driver missense mutations. Cancer Res. 2009, 69, 6660–6667. [Google Scholar] [CrossRef] [PubMed]
  61. Carter, H.; Douville, C.; Stenson, P.D.; Cooper, D.N.; Karchin, R. Identifying Mendelian disease genes with the variant effect scoring tool. BMC Genom. 2013, 14 (Suppl. 3), S3. [Google Scholar] [CrossRef] [PubMed]
  62. Starita, L.M.; Machida, Y.; Sankaran, S.; Elias, J.E.; Griffin, K.; Schlegel, B.P.; Gygi, S.P.; Parvin, J.D. BRCA1-dependent ubiquitination of gamma-tubulin regulates centrosome number. Mol. Cell. Biol. 2004, 24, 8457–8466. [Google Scholar] [CrossRef] [PubMed]
  63. Hsu, L.C.; Doan, T.P.; White, R.L. Identification of a gamma-tubulin-binding domain in BRCA1. Cancer Res. 2001, 61, 7713–7718. [Google Scholar] [PubMed]
  64. Westermark, U.K.; Reyngold, M.; Olshen, A.B.; Baer, R.; Jasin, M.; Moynahan, M.E. BARD1 participates with BRCA1 in homology-directed repair of chromosome breaks. Mol. Cell. Biol. 2003, 23, 7926–7936. [Google Scholar] [CrossRef] [PubMed]
  65. Joukov, V.; Groen, A.C.; Prokhorova, T.; Gerson, R.; White, E.; Rodriguez, A.; Walter, J.C.; Livingston, D.M. The BRCA1/BARD1 heterodimer modulates ran-dependent mitotic spindle assembly. Cell 2006, 127, 539–552. [Google Scholar] [CrossRef] [PubMed]
  66. Zhao, W.; Manley, J.L. Deregulation of poly(A) polymerase interferes with cell growth. Mol. Cell. Biol. 1998, 18, 5010–5020. [Google Scholar] [CrossRef] [PubMed]
  67. Kleiman, F.E.; Manley, J.L. The BARD1-CstF-50 interaction links mRNA 3′ end formation to DNA damage and tumor suppression. Cell 2001, 104, 743–753. [Google Scholar] [CrossRef]
  68. Dechend, R.; Hirano, F.; Lehmann, K.; Heissmeyer, V.; Ansieau, S.; Wulczyn, F.G.; Scheidereit, C.; Leutz, A. The Bcl-3 oncoprotein acts as a bridging factor between NF-κB/Rel and nuclear co-regulators. Oncogene 1999, 18, 3316–3323. [Google Scholar] [CrossRef] [PubMed]
  69. Li, M.; Yu, X. Function of BRCA1 in the DNA damage response is mediated by ADP-ribosylation. Cancer Cell 2013, 23, 693–704. [Google Scholar] [CrossRef] [PubMed]
  70. Feki, A.; Jefford, C.E.; Berardi, P.; Wu, J.Y.; Cartier, L.; Krause, K.H.; Irminger-Finger, I. BARD1 induces apoptosis by catalysing phosphorylation of p53 by DNA-damage response kinase. Oncogene 2005, 24, 3726–3736. [Google Scholar] [CrossRef] [PubMed]
  71. Irminger-Finger, I.; Leung, W.C.; Li, J.; Dubois-Dauphin, M.; Harb, J.; Feki, A.; Jefford, C.E.; Soriano, J.V.; Jaconi, M.; Montesano, R.; et al. Identification of BARD1 as mediator between proapoptotic stress and p53-dependent apoptosis. Mol. Cell 2001, 8, 1255–1266. [Google Scholar] [CrossRef]
  72. Jefford, C.E.; Feki, A.; Harb, J.; Krause, K.H.; Irminger-Finger, I. Nuclear-cytoplasmic translocation of BARD1 is linked to its apoptotic activity. Oncogene 2004, 23, 3509–3520. [Google Scholar] [CrossRef] [PubMed]
  73. Choudhury, A.D.; Xu, H.; Baer, R. Ubiquitination and proteasomal degradation of the BRCA1 tumor suppressor is regulated during cell cycle progression. J. Biol. Chem. 2004, 279, 33909–33918. [Google Scholar] [CrossRef] [PubMed]
  74. Hayami, R.; Sato, K.; Wu, W.; Nishikawa, T.; Hiroi, J.; Ohtani-Kaneko, R.; Fukuda, M.; Ohta, T. Down-regulation of BRCA1-BARD1 ubiquitin ligase by CDK2. Cancer Res. 2005, 65, 6–10. [Google Scholar] [PubMed]
  75. Smith, P.D.; Crossland, S.; Parker, G.; Osin, P.; Brooks, L.; Waller, J.; Philp, E.; Crompton, M.R.; Gusterson, B.A.; Allday, M.J.; et al. Novel p53 mutants selected in BRCA-associated tumours which dissociate transformation suppression from other wild-type p53 functions. Oncogene 1999, 18, 2451–2459. [Google Scholar] [CrossRef] [PubMed]
  76. Phillips, K.A.; Nichol, K.; Ozcelik, H.; Knight, J.; Done, S.J.; Goodwin, P.J.; Andrulis, I.L. Frequency of p53 mutations in breast carcinomas from Ashkenazi Jewish carriers of BRCA1 mutations. J. Natl. Cancer Inst. 1999, 91, 469–473. [Google Scholar] [CrossRef] [PubMed]
  77. Li, L.; Ryser, S.; Dizin, E.; Pils, D.; Krainer, M.; Jefford, C.E.; Bertoni, F.; Zeillinger, R.; Irminger-Finger, I. Oncogenic BARD1 isoforms expressed in gynecological cancers. Cancer Res. 2007, 67, 11876–11885. [Google Scholar] [CrossRef] [PubMed]
  78. Zhang, Y.Q.; Bianco, A.; Malkinson, A.M.; Leoni, V.P.; Frau, G.; De Rosa, N.; Andre, P.A.; Versace, R.; Boulvain, M.; Laurent, G.J.; et al. BARD1: An independent predictor of survival in non-small cell lung cancer. Int. J. Cancer 2012, 131, 83–94. [Google Scholar] [CrossRef] [PubMed]
  79. Feki, A.; Jefford, C.E.; Durand, P.; Harb, J.; Lucas, H.; Krause, K.H.; Irminger-Finger, I. BARD1 expression during spermatogenesis is associated with apoptosis and hormonally regulated. Biol. Reprod. 2004, 71, 1614–1624. [Google Scholar] [CrossRef] [PubMed]
  80. Tsuzuki, M.; Wu, W.; Nishikawa, H.; Hayami, R.; Oyake, D.; Yabuki, Y.; Fukuda, M.; Ohta, T. A truncated splice variant of human BARD1 that lacks the RING finger and ankyrin repeats. Cancer Lett. 2006, 233, 108–116. [Google Scholar] [CrossRef] [PubMed]
  81. Li, L.; Cohen, M.; Wu, J.; Sow, M.H.; Nikolic, B.; Bischof, P.; Irminger-Finger, I. Identification of BARD1 splice-isoforms involved in human trophoblast invasion. Int. J. Biochem. Cell Biol. 2007, 39, 1659–1672. [Google Scholar] [CrossRef] [PubMed]
  82. Tembe, V.; Henderson, B.R. BARD1 translocation to mitochondria correlates with Bax oligomerization, loss of mitochondrial membrane potential and apoptosis. J. Biol. Chem. 2007, 282, 20513–20522. [Google Scholar] [CrossRef] [PubMed]
  83. Dizin, E.; Irminger-Finger, I. Negative feedback loop of BRCA1-BARD1 ubiquitin ligase on estrogen receptor α stability and activity antagonized by cancer-associated isoform of BARD1. Int. J. Biochem. Cell Biol. 2010, 42, 693–700. [Google Scholar] [CrossRef] [PubMed]
  84. Pilyugin, M.; Andre, P.A.; Ratajska, M.; Kuzniacka, A.; Limon, J.; Tournier, B.B.; Colas, J.; Laurent, G.; Irminger-Finger, I. Antagonizing functions of BARD1 and its alternatively spliced variant BARD1δ in telomere stability. Oncotarget 2017, 8, 9339–9353. [Google Scholar] [CrossRef] [PubMed]
  85. Lepore, I.; Dell’Aversana, C.; Pilyugin, M.; Conte, M.; Nebbioso, A.; De Bellis, F.; Tambaro, F.P.; Izzo, T.; Garcia-Manero, G.; Ferrara, F.; et al. HDAC inhibitors repress BARD1 isoform expression in acute myeloid leukemia cells via activation of miR-19a and/or b. PLoS ONE 2013, 8, e83018. [Google Scholar] [CrossRef] [PubMed]
  86. Capasso, M.; Diskin, S.J. Genetics and genomics of neuroblastoma. Cancer Treat. Res. 2010, 155, 65–84. [Google Scholar] [PubMed]
  87. Bryant, H.E.; Schultz, N.; Thomas, H.D.; Parker, K.M.; Flower, D.; Lopez, E.; Kyle, S.; Meuth, M.; Curtin, N.J.; Helleday, T. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005, 434, 913–917. [Google Scholar] [CrossRef] [PubMed]
  88. Ledermann, J.; Harter, P.; Gourley, C.; Friedlander, M.; Vergote, I.; Rustin, G.; Scott, C.L.; Meier, W.; Shapira-Frommer, R.; Safra, T.; et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: A preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2 trial. Lancet Oncol. 2014, 15, 852–861. [Google Scholar] [CrossRef]
  89. Lord, C.J.; Ashworth, A. Mechanisms of resistance to therapies targeting BRCA-mutant cancers. Nat. Med. 2013, 19, 1381–1388. [Google Scholar] [CrossRef] [PubMed]
  90. Ozden, O.; Bishehsari, F.; Bauer, J.; Park, S.H.; Jana, A.; Baik, S.H.; Sporn, J.C.; Staudacher, J.J.; Yazici, C.; Krett, N.; et al. Expression of an oncogenic BARD1 splice variant impairs homologous recombination and predicts response to PARP-1 inhibitor therapy in colon cancer. Sci. Rep. 2016, 6, 26273. [Google Scholar] [CrossRef] [PubMed]
  91. Pilyugin, M.; Descloux, P.; Andre, P.A.; Laszlo, V.; Dome, B.; Hegedus, B.; Sardy, S.; Janes, S.; Bianco, A.; Laurent, G.J.; et al. BARD1 serum autoantibodies for the detection of lung cancer. PLoS ONE 2017, 12, e0182356. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Structure of BRCA1-associated RING domain 1 (BARD1) and spliced isoforms. (A) Full-length (FL) BARD1 exon structure is aligned with spliced BARD1 isoforms below and protein structure above. The protein domains are reported at top of the figure. Splice variants are named with Greek letters (left). Presumed protein coding exons are shown in blue colors; non-coding exons are shown in white (β, κ, γ, η); asterisk shows alternative open reading frames (β, γ and η). Amino acid (aa) number is reported for FL BARD1 and BARD1 isoforms; (B) Model for dual role of BARD1 in cancer. In normal cells BARD1 isoforms (β, δ, ω isoforms, discussed in “Biological Functions of BARD1 as Oncogene” paragraph) are not expressed; in cancer cells, full-length BARD1 (FL) expression (tumor suppressor role of BARD1) decreases and BARD1 isoforms expression (oncogenic role of BARD1) increases. Figure 1 has been modified from Irmgard Irminger-Finger et al. [3].
Figure 1. Structure of BRCA1-associated RING domain 1 (BARD1) and spliced isoforms. (A) Full-length (FL) BARD1 exon structure is aligned with spliced BARD1 isoforms below and protein structure above. The protein domains are reported at top of the figure. Splice variants are named with Greek letters (left). Presumed protein coding exons are shown in blue colors; non-coding exons are shown in white (β, κ, γ, η); asterisk shows alternative open reading frames (β, γ and η). Amino acid (aa) number is reported for FL BARD1 and BARD1 isoforms; (B) Model for dual role of BARD1 in cancer. In normal cells BARD1 isoforms (β, δ, ω isoforms, discussed in “Biological Functions of BARD1 as Oncogene” paragraph) are not expressed; in cancer cells, full-length BARD1 (FL) expression (tumor suppressor role of BARD1) decreases and BARD1 isoforms expression (oncogenic role of BARD1) increases. Figure 1 has been modified from Irmgard Irminger-Finger et al. [3].
Genes 08 00375 g001
Figure 2. BARD1 germline coding mutations. The protein domains RING (green), Ankyrin (ANK, red), BRCA1 carboxy-terminal (BRCT, orange) are indicated. Coding mutations of BARD1 defined as “Pathogenic” and “Likely Pathogenic” in ClinVar database ( are shown. The red arrows indicate the mutations categorized as “Likely Pathogenic”, the other mutations without the arrow are categorized as “Pathogenic”.
Figure 2. BARD1 germline coding mutations. The protein domains RING (green), Ankyrin (ANK, red), BRCA1 carboxy-terminal (BRCT, orange) are indicated. Coding mutations of BARD1 defined as “Pathogenic” and “Likely Pathogenic” in ClinVar database ( are shown. The red arrows indicate the mutations categorized as “Likely Pathogenic”, the other mutations without the arrow are categorized as “Pathogenic”.
Genes 08 00375 g002
Figure 3. Full-length (FL) BARD1 pathways and functions. FL BARD1 participates in two major pathways as tumor suppressor. (A) BRCA1-independent pathways are mediated by the interaction of BARD1 with proteins involved in oncogenic pathways. BARD1 has transcriptional activity as it can induce the transcription activity of NF-κBs through binding to the NF- κB co-factor BCL3 [68]. FL BARD1 interacts to poly(ADP-ribose) (PAR) after damage and consequently it is recruited to DNA repair [69]. Finally, increased expression levels of FL BARD1 stabilize p53 and facilitate its phosphorylation by DNA-dependent protein kinase (DNAPK) [70,71,72]; (B) BRCA1-dependent pathways are mediated by BARD1-BRCA1 heterodimer. The activity of the BARD1-BRCA1 ubiquitin ligase is implicated in essential functions for maintaining genomic stability [61,62,63,64].
Figure 3. Full-length (FL) BARD1 pathways and functions. FL BARD1 participates in two major pathways as tumor suppressor. (A) BRCA1-independent pathways are mediated by the interaction of BARD1 with proteins involved in oncogenic pathways. BARD1 has transcriptional activity as it can induce the transcription activity of NF-κBs through binding to the NF- κB co-factor BCL3 [68]. FL BARD1 interacts to poly(ADP-ribose) (PAR) after damage and consequently it is recruited to DNA repair [69]. Finally, increased expression levels of FL BARD1 stabilize p53 and facilitate its phosphorylation by DNA-dependent protein kinase (DNAPK) [70,71,72]; (B) BRCA1-dependent pathways are mediated by BARD1-BRCA1 heterodimer. The activity of the BARD1-BRCA1 ubiquitin ligase is implicated in essential functions for maintaining genomic stability [61,62,63,64].
Genes 08 00375 g003
Table 1. Pathogenic and Likely pathogenic rare mutations of BARD1 reported in ClinVar database.
Table 1. Pathogenic and Likely pathogenic rare mutations of BARD1 reported in ClinVar database.
Variation IDGRCh37 LocationRef.AltMutation TypeProtein ChangedbSNPFrequency in ExAC DatabaseCondition(s)Clinical Significance (Last Reviewed)
237823...deletion...Familial cancer of breastPathogenic (Last reviewed: 10 December 2015)
230523215593433–215593434TG-frameshift deletionV767fsrs7504134730.00006Familial cancer of breast|not specified|Hereditary cancer-predisposing syndromeConflicting interpretations of pathogenicity (Last reviewed: 18 August 2016)
185366215593466GAnonsenseW756 *rs786202118.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 20 June 2014)
187542215593585–215593586CA-frameshift deletionI717fsrs786203811.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 10 December 2014)
422826215593671AAAframeshift duplicationD689fs..not providedLikely pathogenic (Last reviewed: 29 November 2016)
265365215593734ACsplice acceptor.rs876658260.not providedLikely pathogenic (Last reviewed: 28 June 2016)
229902215593734ATsplice acceptor.rs876658260.Hereditary cancer-predisposing syndromeLikely pathogenic (Last reviewed: 17 November 2015)
182051215595140CTnonsenseQ666 *rs730881422.Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic/Likely pathogenic (Last reviewed: 13 January 2017)
187445215595166C-frameshift deletionP657fsrs786203739.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 3 March 2016)
430952215595182–215595201frameshift duplicationQ652fs..Familial cancer of breastPathogenic (Last reviewed: 13 April 2017)
265510215595182–215595201frameshift deletionC645fsrs886039589.not providedLikely pathogenic (Last reviewed: 3 December 2015)
127725215595182–215595201frameshift duplicationQ652fsrs587780024.Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic/Likely pathogenic (Last reviewed: 13 April 2017)
142499215595203–215595204AT-frameshift deletionC645fsrs587782504.Hereditary cancer-predisposing syndromePathogenic/Likely pathogenic (Last reviewed: 20 November 2015)
141702215595215CTnonsenseR641 *rs5877819480.00001Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 4 October 2016)
232108215595234A-splice acceptor.rs876659560.Hereditary cancer-predisposing syndromeLikely pathogenic (Last reviewed: 29 May 2015)
219763215595234ATsplice acceptor.rs864622239.Familial cancer of breastLikely pathogenic (Last reviewed: 8 August 2015)
233167215609790GTsplice donor.rs876660237.Hereditary cancer-predisposing syndromeLikely pathogenic (Last reviewed: 6 August 2015)
232127215609822T-frameshift deletionL625fsrs876659572.not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 26 July 2016)
143017215609876–215609877AT-frameshift deletionH606fsrs587782897.not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 8 June 2016)
245801215609884GAsplice acceptor.rs879253952.not providedPathogenic (Last reviewed: 9 June 2015)
246449215609885–215609893-splice acceptor.rs879254264.not providedLikely pathogenic (Last reviewed: 7 March 2016)
232643215610445GAsplice donor.rs876659894.Hereditary cancer-predisposing syndromeLikely pathogenic (Last reviewed: 30 June 2015)
127720215610566CTnonsenseQ564*rs5877800210.00005Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 3 January 2017)
406791215617170GCsplice donor.rs1060501310.Familial cancer of breastLikely pathogenic (Last reviewed: 2 August 2016)
141384215617196CGnonsenseS551 *rs587781707.Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 29 December 2016)
230172215617209GTnonsenseE547 *rs876658429.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 28 January 2015)
406768215617214–215617248frameshift indelT534fsrs1064792931.Familial cancer of breastPathogenic (Last reviewed: 22 September 2016)
379750215617226CAnonsenseS541 *rs777937955.not providedPathogenic (Last reviewed: 14 May 2015)
406776215632275-Aframeshift duplicationD500fs..Familial cancer of breastPathogenic (Last reviewed: 13 August 2016)
421820215633955-Gsplice donor duplication...not providedLikely pathogenic (Last reviewed: 4 August 2016)
233414215634002-Aframeshift duplicationN450fsrs876660390.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 17 August 2015)
406748215634026C-frameshift deletionP442fsrs1060501287.Familial cancer of breast|not providedPathogenic/Likely pathogenic (Last reviewed: 20 September 2016)
243116215645314A-frameshift deletionE429fsrs879253879.not providedLikely pathogenic (Last reviewed: 11 December 2015)
234190215645328A-frameshift deletionR424fsrs876660911.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 2 October 2015)
187182215645331–215645334GTGATGframeshift indelV422fsrs786203533.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 10 November 2014)
229677215645382CTnonsenseR406 *rs3771532500.00003Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 11 November 2014)
142734215645386CGnonsenseY404 *rs587782681.Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 13 October 2016)
379884215645393CGnonsenseS402 *rs796666047.not providedPathogenic (Last reviewed: 1 June 2015)
187646215645400A-frameshift deletionS400fsrs786203891.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 17 December 2014)
237814215645426CGnonsenseS391 *rs878853995.Familial cancer of breastPathogenic (Last reviewed: 24 February 2016)
185916215645537CGnonsenseS354 *rs786202559.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 24 March 2016)
232902215645575G-frameshift deletionS342fsrs876660061.not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 21 July 2015)
419156215645584C-frameshift deletionS339fsrs1064793682.not providedPathogenic (Last reviewed: 1 June 2015)
141412215645651TGnonsenseL316 *rs587781728.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 7 April 2014)
185015215645737–215645738AG-frameshift deletionE287fsrs786201868.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 29 May 2014)
232418215645759–215645760TT-frameshift deletionL280fsrs876659752.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 15 June 2015)
406757215645853-Aframeshift duplicationI249fs..Familial cancer of breastPathogenic (Last reviewed: 24 October 2016)
141005215645865CTnonsenseQ245 *rs5877814300.00001not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 8 March 2017)
230107215645889CTnonsenseQ237 *rs587780035.not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 11 July 2016)
141342215645938–215645941TTTA-frameshift deletionR219fsrs587781671.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 23 February 2014)
219726215645970–215645971AA-frameshift deletionK209fsrs864622223.Familial cancer of breast|not providedPathogenic/Likely pathogenic (Last reviewed: 4 December 2015)
127742215645975-Aframeshift deletionK209fsrs587780033.Familial cancer of breast|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 18 November 2016)
182042215645991GTnonsenseG203 *rs730881415.not providedPathogenic (Last reviewed: 25 September 2014)
233965215646006G-frameshift deletionA198fsrs876660761.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 15 September 2015)
186576215646058–215646059AT-frameshift deletionY180fsrs7794276280.00001Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 13 December 2016)
406761215646072CTnonsenseQ176 *rs776851287.Familial cancer of breastPathogenic (Last reviewed: 26 May 2016)
185846215646102CTnonsenseQ166 *rs786202500.not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 4 April 2016)
230344215646138–215646141-AAAGframeshift duplicationV154fsrs772486760.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 2 February 2015)
182036215646150CTnonsenseR150 *rs7308814110.00001Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 29 July 2016)
185139215657051CTnonsenseR112 *rs7589725890.00001Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 27 May 2016)
185079215657087CTnonsenseQ100 *rs786201912.Familial cancer of breast|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 13 December 2016)
230447215657108CTnonsenseQ93 *rs876658571.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 23 February 2015)
231019215657170GAsplice acceptor.rs876658905.Hereditary cancer-predisposing syndromeLikely pathogenic (Last reviewed: 26 March 2015)
371931215661823–215661824AG-frameshift deletionE59fsrs1057517589.Familial cancer of breastPathogenic/Likely pathogenic (Last reviewed: 16 November 2016)
246176215661842GTsplice acceptor.rs879254139.not providedLikely pathogenic (Last reviewed: 3 December 2015)
246476215674192GAnonsenseW34 *rs879254280.not providedLikely pathogenic (Last reviewed: 8 March 2016)
231232215674224–215674225frameshift indelA25fsrs876659040.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 25 March 2015)
233594215674239GTnonsenseE19 *rs7525141550.00002Familial cancer of breast|not provided|Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 28 August 2016)
232926215674271–215674290frameshift deletionP2fsrs876660077.Hereditary cancer-predisposing syndromePathogenic (Last reviewed: 10 July 2015)
127739215674291GAmissenseM1Irs587780031.not providedPathogenic (Last reviewed: 5 November 2013)
154206190300875–242783384..copy number gain (2q32.2-37.3).nssv3395386.HypospadiasPathogenic (Last reviewed: 18 March 2014)
152738193803552–216569775..copy number loss (2q32.3-35).nssv1608180.Developmental delay AND/OR other significant developmental or morphological phenotypesPathogenic (Last reviewed: 14 January 2013)
150620181378520–225167565..copy number gain (2q31.3-36.1).nssv1604018.Developmental delay AND/OR other significant developmental or morphological phenotypesPathogenic (Last reviewed: 25 July 2011)
146683211444400–243059659..copy number gain (2q34-37.3).nssv706486.Coarctation of aortaPathogenic (Last reviewed: 25 February 2011)
59164213479146–227985946..copy number gain (2q34-36).nssv578841.Developmental delay AND/OR other significant developmental or morphological phenotypesPathogenic (Last reviewed: 12 August 2011)
59160193987039–242014395..copy number gain (2q32.3-37.3).nssv578835.Developmental delay AND/OR other significant developmental or morphological phenotypesPathogenic (Last reviewed: 12 August 2011)
59159191175462–242834921..copy number gain (2q32.2-37.3).nssv578834.Developmental delay AND/OR other significant developmental or morphological phenotypesPathogenic (Last reviewed: 12 August 2011)
59158189682921–243007359..copy number gain (2q32.2-37.3).nssv578833.Developmental delay AND/OR other significant developmental or morphological phenotypesPathogenic (Last reviewed: 12 August 2011)
57419195763507–237382556..copy number gain (2q32.3-37.3).nssv578837.Developmental delay AND/OR other significant developmental or morphological phenotypesPathogenic (Last reviewed: 12 August 2011)
*: truncated protein.
Table 2. Somatic mutations of BARD1 deposited in COSMIC database with pathogenicity statistical significance.
Table 2. Somatic mutations of BARD1 deposited in COSMIC database with pathogenicity statistical significance.
PositionSequence OntologyProtein Sequence ChangeCHASM p-ValueVEST p-ValueID dbSNPFrequency in ExAC DatabaseCOSMIC Variant Count in Tissues (n)
214769310SGR123 *0.1290rs3699866490.00large_intestine (1); lung (1); endometrium (1); skin(2)
214781072MSE268K0.27240.43820.00cervix(1); liver(2)
214781454MSK140N0.56200.1730rs7587496030.000008large_intestine(1); endometrium(1)
214781285SGK197 *0.20260.00liver(2)
214781251FDK208RKL *0.05880.000017large_intestine(1)
214728990SGG674 *0.05770.00
214745084SGW629 *0.0191rs7474467110.000008lung(1)
214781361^ FDsee footnote0.20060.000016biliary_tract(1)
214781384SGQ164 *0.14070.00endometrium(1)
214781449SGS142 *0.12720.00endometrium(1)
214728971SGW680 *0.09670.00large_intestine(1)
214792327SGR112 *0.0323rs7589725890.000008large_intestine(1)
214781250FIK208KENFS *0.0618rs5877800330.000017stomach(1)
SG: Stop Gain; MS: Missense; FD: Frameshift Deletion; SY: Synonymous; SS: Splicing Site; FI: Frameshift Insertion; *: truncated proteins; ^: protein deletion K171KMQVLSKTHMNLFPQVLLQMFLRGLKRLLQDLEKSKKRKL; ID dbSNP: Nomenclature of the single nucleotide polymorphism; Exac database ( Exome Aggregation Consortium is a database that reports the frequency of variants from a wide variety of large-scale sequencing projects, CHASM: Cancer-specific High-throughput Annotation of Somatic Mutations; VEST: Variant Effect Scoring Tool.

Share and Cite

MDPI and ACS Style

Cimmino, F.; Formicola, D.; Capasso, M. Dualistic Role of BARD1 in Cancer. Genes 2017, 8, 375.

AMA Style

Cimmino F, Formicola D, Capasso M. Dualistic Role of BARD1 in Cancer. Genes. 2017; 8(12):375.

Chicago/Turabian Style

Cimmino, Flora, Daniela Formicola, and Mario Capasso. 2017. "Dualistic Role of BARD1 in Cancer" Genes 8, no. 12: 375.

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop