Factors predicting reclassification of variants of unknown significance.

Unlabelled: Genetic variants of unknown significance (VUS) are an increasingly common result of genetic testing. VUS present dilemmas for treatment and surveillance. Family history may play a role in VUS reclassification over time.

Methods: All genetic tests performed at a tertiary referral center 2006-2015 were evaluated for the presence of VUS. Patients with VUS were evaluated for demographics, clinical characteristics, family history, and gene characteristics.

Results: In total, 2291 individuals were tested from 1639 families; 150 VUS were identified. Twenty-eight VUS reclassified, 21 to benign and 7 to pathogenic. Logistic regression demonstrated the number of family members with associated phenotypic disease was a significant predictor of reclassification.

Conclusion: The likelihood of VUS reclassification can be predicted by increased positive family history of disease. Most VUS reclassify to benign, but one-fourth reclassify to pathogenic. The actual risk of a VUS should be assessed based on family history and routinely checked for reclassification.