Experience of reassessingFBN1variants of uncertain significance by gene-specific guidelines

Abstract

AbstractBackgroundDespite the 2015 American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guideline, many variants ofFBN1gene remain inconclusive. In line with publication of theFBN1-specific variant interpretation guideline by ClinGen in 2022, we reassessed variants of uncertain significance (VUS) inFBN1gene found in our institution.MethodsVUS found in the course ofFBN1sequencing between December 2015 and April 2022 were reassessed based onFBN1-specific variant interpretation guideline, review of updated literatures and additional genetic tests including family study and/or RNA study if available.ResultsOut of 695 patients who underwentFBN1sequencing, 61 VUS were found in 69 patients. Among them, 38 VUS in 43 patients (62.3%) were reclassified as pathogenic and likely pathogenic variant ((L)PV), including 20 novel (L)PV. Major causes of reclassification were: (1) gene-specific modification of ACMG/AMP criteria, (2) updated literatures and (3) additional genetic tests. The most important evidence for reclassification was clarification of critical amino acid residues.ConclusionsAfter reassessingFBN1variants according toFBN1-specific guideline and up-to-date database, a significant number of VUS was reclassified. Clinical laboratories are encouraged to perform variant reassessment at regular intervals or when there is a major change in the principle of variant interpretation.