Reassessment of the NF1 variants of unknown significance found during the 20-year activity of a genetics diagnostic laboratory

• DOI: 10.1016/j.ejmg.2023.104847
• Publication Date: 2023-09-24T21:48:36Z
• Authors: Davide Martorana; Valeria Barili; Vera Uliana; Enrico Ambrosini; Matteo Riva; Erika De Sensi; Elena Luppi; Corinne Messina; Edoardo Caleffi; Francesco Pisani; Antonio Percesepe
• Keywords: Penetrance; Medical genetics; Genetic diagnosis

The finding of variants uncertain significance (VUS) in the activity a diagnostic genetic laboratory is common issue, which however provisional and needs to be periodically re-evaluated, due continuous advancements our knowledge diseases. Neurofibromatosis type 1, caused by occurrence heterozygous pathogenic NF1 variants, good model for studying evolution VUS, widespread use testing disease, constant enrichment international databases with full adult penetrance makes genotyping parents crucial step workflow. present study retrospectively reviewed reinterpreted test results period from January 2000 December 31, 2020. All VUS were using 2015 consensus standards guidelines interpretation. Out 589 tests performed period, total 85 found 72 cases (84.7%): 21 (29.2%) reclassified as benign/likely benign, whereas 51 (70.8%) recoded pathogenic/likely significant trend distribution (Chi square p = 0.005). Synonymous have mainly been class 1 2 (7/8, 87.5%), missense attributed 4 5 38 out 58 (65.5%). These findings underline an improvement classification over time, suggesting that reinterpretation should routinely support physicians clinical diagnosis