title: A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS).
abstract: Clinical mutation screening of the BRCA1 and BRCA2 genes for the presence of germline inactivating mutations is used to identify individuals at elevated risk of breast and ovarian cancer. Variants identified during screening are usually classified as pathogenic (increased risk of cancer) or not pathogenic (no increased risk of cancer). However, a significant proportion of genetic tests yields variants of uncertain significance (VUS) that have undefined risk of cancer. Individuals carrying these VUS cannot benefit from individualized cancer risk assessment. Recently, a quantitative "posterior probability model" for assessing the clinical relevance of VUS in BRCA1 or BRCA2, which integrates multiple forms of genetic evidence has been developed. Here, we provide a detailed review of this model. We describe the components of the model and explain how these can be combined to calculate a posterior probability of pathogenicity for each VUS. We explain how the model can be applied to public data and provide tables that list the VUS that have been classified as not pathogenic or pathogenic using this method. While we use BRCA1 and BRCA2 VUS as examples, the method can be used as a framework for classification of the pathogenicity of VUS in other cancer genes.
authors: Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors: Noralane M
authors: NM
authors: Lindor
authors: Lucia
authors: L
authors: Guidugli
authors: Xianshu
authors: X
authors: Wang
authors: Maxime P
authors: MP
authors: Vallée
authors: Alvaro N A
authors: AN
authors: Monteiro
authors: Sean
authors: S
authors: Tavtigian
authors: David E
authors: DE
authors: Goldgar
authors: Fergus J
authors: FJ
authors: Couch
mesh_terms: D000328:Adult; D000483:Alleles; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics; D003062:Codon; D005091:Exons; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D014644:Genetic Variation; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D015233:Models, Statistical; D010051:Ovarian Neoplasms / Q000175:diagnosis* / Q000235:genetics; D011336:Probability; D011379:Prognosis; D012307:Risk Factors; D035501:Uncertainty
chemical_list: D003062:Codon