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Functional redundancy of Exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A > G (p.I2285V) variant

(2009) HUMAN MUTATION. 30(11). p.1543-1550
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Abstract
Variants of unknown significance (VUS) in BRCA1 and BRCA2 are common, and present significant challenges for genetic counseling. We observed that BRCA2: c.6853A>G (p.I2285V) (Breast Cancer Information Core [BIC] name: 7081A > G; http://research.nhgri.nih.gov/bic/) co-occurs in trans with the founder mutation c.5946delT (p.S1982RfsX22) (BIC name: 6174deIT), supporting the published classification of p.I2285V as a neutral variant. However, we also noted that when compared with wild,type BRCA2, p.I2285V resulted in increased exclusion of exon 12. Functional assay using allelic complementation in Brca2-null mouse embryonic stern cells revealed that p.I2285V, an allele with exon 12 deleted and wild-type BRCA2 were all phenotypically indistinguishable, as measured by sensitivity to DNA-damaging agents, effect on irradiation-induced Rad51. foci formation, homologous recombination, and overall genontic integrity. An allele frequency study showed the p.I2285V variant was identified in 15 out of 722 (2.1%) Ashkenazi Jewish cases and 10 out of 475 (2.1%) ethnically,matched controls (odds ratio, 0.99; 95% confidence interval: 0.44-2.21; P = 0.97). Thus the p.I2285V variant is not associated with an increased risk for breast cancer. Taken together, our clinical and functional studies strongly suggest that exon 12 is functionally redundant and therefore missense variants in this exon are likely to be neutral. Such comprehensive functional studies will be important adjuncts to genetic studies of variants. Hum Mutat 30:1543-1550, 2009. Published 2009 Wiley-Liss, Inc.
Keywords
BREAST-CANCER, ES cells, ESE, exon splicing enhancer, VUS, unclassified variants, BRCA2, MISSENSE SUBSTITUTIONS, CLINICAL-SIGNIFICANCE, MUTATIONS, CLASSIFICATION, GENES, NONSENSE, OVARIAN, REPAIR

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Citation

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MLA
Li, Li LL, Kajal Biswas, Laura Anne Habib, et al. “Functional Redundancy of Exon 12 of BRCA2 Revealed by a Comprehensive Analysis of the c.6853A > G (p.I2285V) Variant.” HUMAN MUTATION 30.11 (2009): 1543–1550. Print.
APA
Li, L. L., Biswas, K., Habib, L. A., Kuznetsov, S. G., Hamel, N., Kirchhoff, T., Wong, N., et al. (2009). Functional redundancy of Exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A > G (p.I2285V) variant. HUMAN MUTATION, 30(11), 1543–1550.
Chicago author-date
Li, Li LL, Kajal Biswas, Laura Anne Habib, Sergey G Kuznetsov, Nancy Hamel, Tomas Kirchhoff, Nora Wong, et al. 2009. “Functional Redundancy of Exon 12 of BRCA2 Revealed by a Comprehensive Analysis of the c.6853A > G (p.I2285V) Variant.” Human Mutation 30 (11): 1543–1550.
Chicago author-date (all authors)
Li, Li LL, Kajal Biswas, Laura Anne Habib, Sergey G Kuznetsov, Nancy Hamel, Tomas Kirchhoff, Nora Wong, Susan Armel, George Chong, SA Narod, Kathleen Claes, Kenneth Offit, Mark E Robson, Stacey Stauffer, Shyam K Sharan, and William D Foulkes. 2009. “Functional Redundancy of Exon 12 of BRCA2 Revealed by a Comprehensive Analysis of the c.6853A > G (p.I2285V) Variant.” Human Mutation 30 (11): 1543–1550.
Vancouver
1.
Li LL, Biswas K, Habib LA, Kuznetsov SG, Hamel N, Kirchhoff T, et al. Functional redundancy of Exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A > G (p.I2285V) variant. HUMAN MUTATION. 2009;30(11):1543–50.
IEEE
[1]
L. L. Li et al., “Functional redundancy of Exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A > G (p.I2285V) variant,” HUMAN MUTATION, vol. 30, no. 11, pp. 1543–1550, 2009.
@article{1169919,
  abstract     = {Variants of unknown significance (VUS) in BRCA1 and BRCA2 are common, and present significant challenges for genetic counseling. We observed that BRCA2: c.6853A>G (p.I2285V) (Breast Cancer Information Core [BIC] name: 7081A > G; http://research.nhgri.nih.gov/bic/) co-occurs in trans with the founder mutation c.5946delT (p.S1982RfsX22) (BIC name: 6174deIT), supporting the published classification of p.I2285V as a neutral variant. However, we also noted that when compared with wild,type BRCA2, p.I2285V resulted in increased exclusion of exon 12. Functional assay using allelic complementation in Brca2-null mouse embryonic stern cells revealed that p.I2285V, an allele with exon 12 deleted and wild-type BRCA2 were all phenotypically indistinguishable, as measured by sensitivity to DNA-damaging agents, effect on irradiation-induced Rad51. foci formation, homologous recombination, and overall genontic integrity. An allele frequency study showed the p.I2285V variant was identified in 15 out of 722 (2.1%) Ashkenazi Jewish cases and 10 out of 475 (2.1%) ethnically,matched controls (odds ratio, 0.99; 95% confidence interval: 0.44-2.21; P = 0.97). Thus the p.I2285V variant is not associated with an increased risk for breast cancer. Taken together, our clinical and functional studies strongly suggest that exon 12 is functionally redundant and therefore missense variants in this exon are likely to be neutral. Such comprehensive functional studies will be important adjuncts to genetic studies of variants. Hum Mutat 30:1543-1550, 2009. Published 2009 Wiley-Liss, Inc.},
  author       = {Li, Li LL and Biswas, Kajal and Habib, Laura Anne and Kuznetsov, Sergey G and Hamel, Nancy and Kirchhoff, Tomas and Wong, Nora and Armel, Susan and Chong, George and Narod, SA and Claes, Kathleen and Offit, Kenneth and Robson, Mark E and Stauffer, Stacey and Sharan, Shyam K and Foulkes, William D},
  issn         = {1059-7794},
  journal      = {HUMAN MUTATION},
  keywords     = {BREAST-CANCER,ES cells,ESE,exon splicing enhancer,VUS,unclassified variants,BRCA2,MISSENSE SUBSTITUTIONS,CLINICAL-SIGNIFICANCE,MUTATIONS,CLASSIFICATION,GENES,NONSENSE,OVARIAN,REPAIR},
  language     = {eng},
  number       = {11},
  pages        = {1543--1550},
  title        = {Functional redundancy of Exon 12 of BRCA2 revealed by a comprehensive analysis of the c.6853A > G (p.I2285V) variant},
  url          = {http://dx.doi.org/10.1002/humu.21101},
  volume       = {30},
  year         = {2009},
}

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