title: Comparative analysis of BRCA1 and BRCA2 variants of uncertain significance in patients with breast cancer: a multifactorial probability-based model versus ACMG standards and guidelines for interpreting sequence variants.
abstract: To investigate variants of uncertain significance (VUS) in BRCA1 and BRCA2, we assessed the multifactorial posterior probability of VUS in BRCA1 and BRCA2 and compared these analyses with interpretations according to the recently released American College of Medical Genetics and Genomics (ACMG) standards and guidelines.
  
  
  
  The analysis involved 715 Korean patients with breast cancer. The multifactorial probability of a VUS was analyzed using the prior probability and combined likelihoods of personal and family history, the pathologic profile of the breast cancer, and co-occurrence with pathogenic variants. Results were compared with those obtained according to the ACMG standards/guidelines.
  
  
  
  Sixteen VUS from 51 BRCA1 VUS carriers and 28 VUS from 62 BRCA2 VUS carriers were analyzed. There was a slight agreement between the two analyses, with a kappa value of 0.14 (95% confidence interval (CI) = -0.34 to 0.62) for the BRCA1 VUS and a kappa value of 0.17 (95% CI = -0.10 to 0.49) for the BRCA2 VUS.
  
  
  
  We propose that genetic counseling should be based on the concordant results between these two analyses. When discrepancies are found, those variants are still considered VUS and careful counseling should be provided.Genet Med 18 12, 1250-1257.
authors.affiliation: SD Genomics Co., Ltd., Seoul, Korea.
authors.forename: Kyung Sun
authors.identifier: 0000-0001-6714-6619
authors.initials: KS
authors.lastname: Park
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Eun Yoon
authors.identifier: 0000-0003-4675-4492
authors.initials: EY
authors.lastname: Cho
authors.affiliation: Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Seok Jin
authors.initials: SJ
authors.lastname: Nam
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Jong-Won
authors.identifier: 0000-0002-0708-9242
authors.initials: JW
authors.lastname: Kim
mesh_terms: D019313:BRCA1 Protein / Q000235:genetics*; D024682:BRCA2 Protein / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D005260:Female; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D017408:Guidelines as Topic; D006801:Humans; D009154:Mutation; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human