title: Classification and Clinical Management of Variants of Uncertain Significance in High Penetrance Cancer Predisposition Genes.
abstract: In 2008, the International Agency for Research on Cancer (IARC) proposed a system for classifying sequence variants in highly penetrant breast and colon cancer susceptibility genes, linked to clinical actions. This system uses a multifactorial likelihood model to calculate the posterior probability that an altered DNA sequence is pathogenic. Variants between 5%-94.9% (class 3) are categorized as variants of uncertain significance (VUS). This interval is wide and might include variants with a substantial difference in pathogenicity at either end of the spectrum. We think that carriers of class 3 variants would benefit from a fine-tuning of this classification. Classification of VUS to a category with a defined clinical significance is very important because for carriers of a pathogenic mutation full surveillance and risk-reducing surgery can reduce cancer incidence. Counselees who are not carriers of a pathogenic mutation can be discharged from intensive follow-up and avoid unnecessary risk-reducing surgery. By means of examples, we show how, in selected cases, additional data can lead to reclassification of some variants to a different class with different recommendations for surveillance and therapy. To improve the clinical utility of this classification system, we suggest a pragmatic adaptation to clinical practice.
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, 2333 ZA, The Netherlands.
authors.forename: Setareh
authors.initials: S
authors.lastname: Moghadasi
authors.affiliation: Faculty of Medicine, University of Southampton, Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, SO16 5YA, United Kingdom.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Eccles
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, 2333 ZC, The Netherlands.
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, 2333 ZC, The Netherlands.
authors.forename: Maaike P G
authors.initials: MP
authors.lastname: Vreeswijk
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, 2333 ZA, The Netherlands.
authors.forename: Christi J
authors.initials: CJ
authors.lastname: van Asperen
mesh_terms: D019468:Disease Management; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D014644:Genetic Variation; D006801:Humans; D015233:Models, Statistical; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D019683:Penetrance; D017410:Practice Guidelines as Topic; D035501:Uncertainty
keywords: cancer predisposition genes; clinical management; multifactorial likelihood model (MLM); variants of uncertain significance (VUS)