Family Studies for Classification of Variants of Uncertain Classification: Current Laboratory Clinical Practice and a New Web-Based Educational Tool.

Lauren T Garrett,Brian H Shirts,Elisabeth A Rosenthal,Angela Jacobson,Robin L Bennett,Laura M Amendola,Nathan Hickman

doi:10.1007/s10897-016-9993-2

Abstract

Multi-gene cancer panels often identify variants of uncertain clinical significance (VUS) that pose a challenge to health care providers in managing a patient’s cancer risk. Family segregation analysis can yield powerful data to re-classify a VUS (as either benign or pathogenic). However, financial and personnel resources to coordinate these studies are limited. In an informal assessment we found that family studies for variant classification are done by most clinical genetics laboratories that offer hereditary cancer panel testing. The process for family studies differs substantially across laboratories. One near universal limitation is that families usually have too few individuals for an informative co-segregation analysis. A unique and potential resource-saving approach is to engage patients and their families in expanding their own pedigrees for segregation analysis of their VUS. We describe a novel public educational tool (FindMyVariant.org) designed to inform patients and genetic counselors about strategies to improve the probability of variant classification using familial segregation. While the web tool is designed to be useful for any gene, the project was primarily focused on VUS’s returned in cancer risk genes. FindMyVariant.org is a resource for genetic providers to offer motivated families who are willing to gather information about their family relationships and history. Working alongside clinical or research genetic laboratories, the information they collect may help reclassify their VUS using segregation analysis.

Highlights

Panel gene sequencing has become an increasingly important strategy for evaluating inherited disease risk
These panels have the caveat of identifying rare variants of uncertain clinical significance (VUS) in a higher proportion of patients compared to single gene testing alone (Cragun et al 2014; Kurian et al 2014; Maron et al 2012; Maxwell et al 2014; Tung et al 2014)
In response to needs of patients with VUS reports and genetics providers who may be interested in family studies to classify VUS, we developed a novel public educational tool designed to inform patients and genetic counselors about strategies to improve the probability of VUS re-classification using familial segregation

Summary

Introduction

Panel gene sequencing has become an increasingly important strategy for evaluating inherited disease risk. Expanded gene panels are more sensitive than single gene testing, and are often more cost effective than sequential testing, leading to additional diagnostic and prevention opportunities (Gallego et al 2015) These panels have the caveat of identifying rare variants of uncertain clinical significance (VUS) in a higher proportion of patients compared to single gene testing alone (Cragun et al 2014; Kurian et al 2014; Maron et al 2012; Maxwell et al 2014; Tung et al 2014). A VUS typically has some characteristics or associated data indicating the variant may be deleterious, but not enough information to definitively classify it as disease causing, or pathogenic. Millions of such variants are present at low frequencies in the population (Lek et al 2015)

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