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Abstract
Purpose
Family studies are an important but underreported source of information for reclassification of variants of uncertain significance (VUS). We evaluated outcomes of a patient-driven framework that offered familial VUS reclassification analysis to any adult with any clinically ascertained VUS from any laboratory in the United States.
Methods
With guidance from FindMyVariant.org, participants recruited their own relatives for study participation. We genotyped relatives, calculated quantitative cosegregation likelihood ratios, and evaluated variant classifications using Tavtigian’s unified framework for Bayesian analysis with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) criteria. We report participation and VUS reclassification rates from the 50 families enrolled for at least one year and reclassification results for 112 variants from the larger 92-family cohort.
Results
For the 50-family cohort, 6.7 relatives per family were invited to participate and 67% of relatives returned samples for genotyping. Sixty-one percent of VUS were reclassified, 84% of which were classified as benign or likely benign. Genotyping relatives identified a de novo variant, phase variants, and relatives with phenotypes highly specific for or incompatible with specific classifications.
Conclusions
Motivated families can contribute to successful VUS reclassification at substantially higher rates than those previously published. Clinical laboratories could consider offering family studies to all patients with VUS.
Details
1 Department of Laboratory Medicine, University of Washington, Seattle, WA, USA
2 Department of Biomedical Informatics and Medical Education, University of Washington, Seattle, WA, USA
3 Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA, USA
4 Department of Bioethics and Humanities, University of Washington, Seattle, WA, USA