Classification and Clinical Management of Variants of Uncertain Significance in High Penetrance Cancer Predisposition Genes

Human Mutation
Setareh MoghadasiChristi J van Asperen

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 ut...Continue Reading

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Citations

Apr 17, 2020·Breast Cancer Research : BCR·Cédric Van MarckeFrançois P Duhoux
Jun 13, 2018·Journal of Clinical Medicine·Simon GarinetJean-Baptiste Oudart
Mar 5, 2020·Journal of Experimental & Clinical Cancer Research : CR·Giulia Federici, Silvia Soddu
Dec 17, 2020·International Journal of Molecular Sciences·Paola De SimonePaola Grammatico
Jan 26, 2021·The Application of Clinical Genetics·Lindsey McAlarnenDenise Uyar
Aug 5, 2021·Inflammatory Bowel Diseases·Giuseppe BiscagliaOrazio Palmieri

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