title: Variants of uncertain significance in BRCA1 and BRCA2 assessment of in silico analysis and a proposal for communication in genetic counselling.
abstract: BACKGROUND
  Nearly 15% of BRCA1 and BRCA2 DNA tests lead to the identification of Variants of Uncertain Significance (VUS). VUS are classified in the Netherlands according to the Bell system and it is current practice that class III VUS are communicated to counsellees, but not class II or lower VUS. Our aims were to investigate the utility of in silico characteristics in the classification of VUS and whether initial VUS classifications justify differences in communication protocols during counselling.
  
  
  METHODS
  We classified 88 missense VUS in BRCA1 and BRCA2 on the basis of an in silico analysis and compared the classification of a subset of 60 VUS of which additional information including family, genetic and tumour data was available.
  
  
  RESULTS
  VUS allocated to class III more frequently showed in silico indications of a deleterious effect than class II VUS. Of the 46 VUS assigned to class II by in silico analysis alone, nearly half were eventually recategorised as class I and 10% as class III when additional information was included.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Setareh
authors.initials: S
authors.lastname: Moghadasi
authors.forename: Nandy
authors.initials: N
authors.lastname: Hofland
authors.forename: Joyce N
authors.initials: JN
authors.lastname: Wouts
authors.forename: Frans B L
authors.initials: FB
authors.lastname: Hogervorst
authors.forename: Juul T
authors.initials: JT
authors.lastname: Wijnen
authors.forename: Maaike P G
authors.initials: MP
authors.lastname: Vreeswijk
authors.forename: Christi J
authors.initials: CJ
authors.lastname: van Asperen
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D019313:BRCA1 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D024682:BRCA2 Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D003198:Computer Simulation; D005260:Female; D005817:Genetic Counseling; D005820:Genetic Testing; D006801:Humans; D020125:Mutation, Missense; D010051:Ovarian Neoplasms / Q000235:genetics; D011237:Predictive Value of Tests; D016415:Sequence Alignment
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human