Cancer-Associated Mutations in BRC Domains of BRCA2 Affect Homologous Recombination Induced by Rad51

Tal, Asaf; Arbel-Goren, Rinat; Stavans, Joel

doi:10.1016/j.jmb.2009.09.011

Cited by 29 publications

(30 citation statements)

References 34 publications

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“…In a recent publication by Lindor et al 20 for example, the BRCA2 variant c.4585G>A; p.Gly1529Arg is categorised as class I, based on an article by Easton et al 21. However, this variant is registered in the LOB database as a class III variant, because the biological effect of this mutation has clearly been shown by Tal et al 22. Although Dutch molecular geneticists generally use the Bell classification system and Lindor et al 20 have used the Plon classification (table 1), the discrepancy in the classification of these variants remains striking and shows that considerable effort and regular meetings at national and international levels are still required to reach a uniform and updated consensus.…”

Section: Discussionmentioning

confidence: 99%

Variants of Uncertain Significance inBRCA1andBRCA2assessment of in silico analysis and a proposal for communication in genetic counselling

et al. 2012

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As in silico analysis alone is not always sufficient to unambiguously assign VUS to either class II or class III, we would argue that the prospect of obtaining additional information from a family should be given more weight during the decision process preceding the communication of a VUS test result. Research initiatives such as the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), which strive to combine diverse sources of information, will be valuable in aiding a definitive classification of a VUS.

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Section: Discussionmentioning

confidence: 99%

Variants of Uncertain Significance inBRCA1andBRCA2assessment of in silico analysis and a proposal for communication in genetic counselling

et al. 2012

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“…A Polyphen and Grantham algorithm analyses which is based on chemical characteristics and molecular volume of the amino acids involved, predicted that this mutation could be deleterious [49]. Moreover, G1529R has been recently reported to impair the ability of BRCA2 to recruit RAD51, which was inferred to hamper DNA repair by homologous recombination [50]. The index cases of both families with the same E3002K variant were diagnosed at 26 and 33 years of age, where both cases inherited these alleles from their affected mothers.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer

et al. 2010

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Few studies have reported on the comprehensive BRCA1/2 mutation analyses of hereditary breast cancer (HBC) families of French Canadian descent. Here we report the investigation of 82 families with at least 3 cases of breast cancer evaluated for mutations by DNA sequencing and/or multiplex ligation-dependent probe amplification (MLPA) assay. DNA sequencing identified pathogenic mutations in 37 (45.1%) families, of which 70.2% were one of three recurring mutations (BRCA1:R1443X, BRCA2:8765delAG, and BRCA2:E1953X) frequently reported in this founder population; and variants of uncertain clinical significance in 7 (8.5%) families of which two harbored BRCA2:E3002K. MLPA analysis of the 38 DNA sequence-negative families did not reveal any large rearrangements in BRCA1/2. A phenotypic characterization of the cancer families based on pathogenic mutation status revealed that there were significantly fewer very young age at diagnosis breast cancer cases (<36 years) in mutation-negative families (5.9%, 9 of 153) than in BRCA1 (22.8%, 13 of 57; P = 0.0003) or BRCA2 (22.9%, 27 of 118; P < 1× 10E5) mutation-positive families. There were significantly more mutation-positive families (29 of 36, 80.6%) with a very young age of onset of breast cancer case than those that did not (8 of 39, 20.5%) (P < 10E6). The comprehensive mutation analysis of BRCA1/2 suggests that genomic rearrangements are unlikely to account for sequence-negative HBC families and affirms that the presence of a very young age of diagnosis of breast cancer is strongly predictive of mutation carrier status of French Canadian HBC families.

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“…All animal experiments were approved by the Experimental Animal Ethics Committee of Nippon Veterinary and Life Science University. The blood samples were originally collected at the Veterinary phisms have not been reported for canine BRC4, although we and others reported that mutations of BRC4 found in human breast cancer patients abolished the interaction with RAD51 (11,14,18). To extend our knowledge of the physiological functions of BRCA2 BRC repeats, and to utilize dogs as a model of human breast cancer, we investigated polymorphic alleles of BRC3 and 4 in multiple dog breeds.…”

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<b>Polymorphisms of canine BRCA2 BRC repeats affecting interaction with </b><b>RAD51 </b>

et al. 2015

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Mutations in the breast cancer susceptibility gene BRCA2 leading to the failure of interactions with the recombinase RAD51 are associated with an increased risk of cancer in humans. This interaction depends on the eight BRC repeat (BRC1-8) sequences in BRCA2. We previously reported that canine BRC3 has two polymorphisms (T1425P and K1435R) influencing the interaction with RAD51, and 1435R was identified in mammary tumor dog samples. In this study, we investigated the sequence variations of BRC3 and 4 in 236 dogs of five breeds. Allele frequencies of 1425P and 1435R were 0.063 and 0.314, respectively, and there was no other polymorphism in the sequenced region. A mammalian two-hybrid assay using BRC3-4 sequences demonstrated that 1425P allele reduced the binding strength with RAD51 but 1435R had no effect. These results may provide an insight into the functions of not only individual but also multiple BRC repeats of BRCA2 in dogs.In humans, the predisposition to heritable breast and ovarian cancers is associated with mutations in the breast cancer susceptibility gene BRCA2 (7). The BRCA2 protein plays an important role in the homologous recombination repair (HR) of doublestranded DNA breaks (DSBs) (7) and promotes the assembly of RAD51 recombinase onto single-stranded DNA (6). To initiate DSB repair by HR, BRCA2 interacts with RAD51 at the highly conserved BRC repeats (BRC) of BRCA2, which consist of 13 conserved amino acid (aa) residues (1). Among eight BRC repeats (BRC1-8), BRC3 and BRC4 are two best-characterized ones exhibiting strong interaction with RAD51 (10,18,21). Mammary tumors are the most common neoplasia in female dogs, and are highly prevalent in certain dog breeds (17). It has been reported that BRCA2 mutations are associated with the development of mammary tumors in dogs (4, 12). We cloned and sequenced canine BRCA2 and found polymorphisms in the putative functional regions containing BRC repeats and nuclear localization signals

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Cancer-Associated Mutations in BRC Domains of BRCA2 Affect Homologous Recombination Induced by Rad51

Cited by 29 publications

References 34 publications

Variants of Uncertain Significance inBRCA1andBRCA2assessment of in silico analysis and a proposal for communication in genetic counselling

Variants of Uncertain Significance inBRCA1andBRCA2assessment of in silico analysis and a proposal for communication in genetic counselling

Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer

<b>Polymorphisms of canine BRCA2 BRC repeats affecting interaction with </b><b>RAD51 </b>

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