Experience of reassessing variants of uncertain significance by gene-specific guidelines.

BACKGROUND

Despite the 2015 American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) guideline, many variants of gene remain inconclusive. In line with publication of the specific variant interpretation guideline by ClinGen in 2022, we reassessed variants of uncertain significance (VUS) in gene found in our institution.

METHODS

VUS found in the course of sequencing between December 2015 and April 2022 were reassessed based on -specific variant interpretation guideline, review of updated literatures and additional genetic tests including family study and/or RNA study if available.

RESULTS

Out of 695 patients who underwent 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.

CONCLUSIONS

After reassessing variants according to -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.