title: Characterization of BRCA1 and BRCA2 variants in multi-ethnic Asian cohort from a Malaysian case-control study.
abstract: Genetic testing for BRCA1 and BRCA2 has led to the accurate identification of individuals at higher risk of cancer and the development of new therapies. Approximately 10-20% of the genetic testing for BRCA1 and BRCA2 leads to the identification of variants of uncertain significance (VUS), with higher proportions in Asians. We investigated the functional significance of 7 BRCA1 and 25 BRCA2 variants in a multi-ethnic Asian cohort using a case-control approach.
  
  
  
  The MassARRAY genotyping was conducted in 1,394 Chinese, 406 Malay and 310 Indian breast cancer cases and 1,071 Chinese, 167 Malay and 255 Indian healthy controls. The association of individual variant with breast cancer risk was analyzed using logistic regression model adjusted for ethnicity, age and family history.
  
  
  
  Our study confirmed BRCA2 p.Ile3412Val is presented in >2% of unaffected women and is likely benign, and BRCA2 p.Ala1996Thr which is predicted to be likely pathogenic by in-silico models is presented in 2% of healthy Indian women suggesting that it may not be associated with breast cancer risk. Single-variant analysis suggests that BRCA1 p.Arg762Ser may be associated with breast cancer risk (OR = 7.4; 95% CI, 0.9-62.3; p = 0.06).
  
  
  
  Our study shows that BRCA2 p.Ile3412Val and p.Ala1996Thr are likely benign and highlights the need for population-specific studies to determine the likely functional significance of population-specific variants. Our study also suggests that BRCA1 p.Arg762Ser may be associated with increased risk of breast cancer but other methods or larger studies are required to determine a more precise estimate of breast cancer risk.
authors.affiliation: Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
authors.forename: Kah Nyin
authors.initials: KN
authors.lastname: Lai
authors.affiliation: Department of Applied Mathematics, Faculty of Engineering, The University of Nottingham Malaysia Campus, 43500, Semenyih, Selangor, Malaysia.
authors.forename: Weang Kee
authors.initials: WK
authors.lastname: Ho
authors.affiliation: Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
authors.forename: In Nee
authors.initials: IN
authors.lastname: Kang
authors.affiliation: Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
authors.forename: Peter Choon Eng
authors.initials: PC
authors.lastname: Kang
authors.affiliation: Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
authors.forename: Sze Yee
authors.initials: SY
authors.lastname: Phuah
authors.affiliation: Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
authors.forename: Shivaani
authors.initials: S
authors.lastname: Mariapun
authors.affiliation: Subang Jaya Medical Centre, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia.
authors.forename: Cheng-Har
authors.initials: CH
authors.lastname: Yip
authors.affiliation: Breast Cancer Research Unit, University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, 50603, Kuala Lumpur, Malaysia.|Department of Surgery, Faculty of Medicine, University Malaya Medical Centre, 50603, Kuala Lumpur, Malaysia.
authors.forename: Nur Aishah
authors.initials: NA
authors.lastname: Mohd Taib
authors.affiliation: Cancer Research Malaysia, 1 Jalan SS12/1A, 47500, Subang Jaya, Selangor, Malaysia. soohwang.teo@cancerresearch.my.|Breast Cancer Research Unit, University Malaya Cancer Research Institute, Faculty of Medicine, University Malaya Medical Centre, University Malaya, 50603, Kuala Lumpur, Malaysia. soohwang.teo@cancerresearch.my.|Department of Surgery, Faculty of Medicine, University Malaya Medical Centre, 50603, Kuala Lumpur, Malaysia. soohwang.teo@cancerresearch.my.
authors.forename: Soo-Hwang
authors.identifier: 0000-0002-0444-590X
authors.initials: SH
authors.lastname: Teo
mesh_terms: D019943:Amino Acid Substitution; D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000208:ethnology / Q000235:genetics*; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008296:Malaysia / Q000208:ethnology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human
keywords: Asia; BRCA1; BRCA2; Malaysia; Variant of uncertain significance