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Outcomes of 92 patient-driven family studies for reclassification of variants of uncertain significance




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.


With guidance from, 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.


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.


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.

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We thank the many families who participated actively as partners in this work. We also thank the undergraduate students who assisted in genotyping: Kimberly Krupa, Sarah Upham, Yijun Sim, Lisa Williamson, Nela Novákova, and Sarah Helfen. We thank Eric Konnick, Moon Chung, David Fareti, Jailanie Kaganovsky, and Gynevill Villanueva for their assistance in processing samples. This study was supported by grants from the Damon Runyon Cancer Research Foundation (DRR-33-15), the National Human Genome Research Institute (NHGRI) (R21HG008513), and the Fred Hutch/University of Washington Cancer Consortium (NCI 5P30 CA015704-39).

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The authors declare no conflicts of interest.

Correspondence to Brian H. Shirts MD, PhD.

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