Experience of reassessing <i>FBN1</i> variants of uncertain significance by gene-specific guidelines.

Abstract

Despite the 2015 American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guideline, many variants of <i>FBN1</i> gene remain inconclusive. In line with publication of the <i>FBN1-</i>specific variant interpretation guideline by ClinGen in 2022, we reassessed variants of uncertain significance (VUS) in <i>FBN1</i> gene found in our institution. VUS found in the course of <i>FBN1</i> sequencing between December 2015 and April 2022 were reassessed based on <i>FBN1</i>-specific variant interpretation guideline, review of updated literatures and additional genetic tests including family study and/or RNA study if available. Out of 695 patients who underwent <i>FBN1</i> sequencing, 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. After reassessing <i>FBN1</i> variants according to <i>FBN1</i>-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.