Determination of Pathogenicity of Gene Variants using the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines.

Objectives: Molecular diagnostic laboratories screen for mutations in disease-causing genes in order to confirm a clinical diagnosis. The classification of DNA variants as 'pathogenic' or 'likely pathogenic' mutations creates a workflow bottleneck, which becomes increasingly challenging as greater number of genes are screened. The classification challenge is also acute if there are conflicting reports regarding pathogenicity and differing classification criteria between laboratories. This study aimed to compare two procedures for the classification of variants in the () gene.

Methods: This bioinformatic study was conducted at LabPLUS, Auckland, New Zealand, from February to June 2017. DNA was extracted from peripheral blood samples of 30 patients and gene library construction was carried out using a commercially available targeted panel for the and genes. The genes were subsequently sequenced and the sequence data analysed. The guidelines published by the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) provides a comprehensive framework for the interpretation of variants in genes that are associated with Mendelian disorders. The use of these guidelines were compared to the variant classifications that were achieved by reference to those reported in the BRCA Exchange database.

Results: The results showed concordance between the two classification protocols for a panel of 30 gene variants, although the transparency in following the ACMG/AMP guidelines provides a diagnostic laboratory with a generalisable approach that allows laboratory-directed revisions to be undertaken in light of new information.

Conclusion: The ACMG/AMP-based guidelines were applied to a cohort of patients with gene variants. The use of these guidelines provides a system which creates consistency in variant interpretation and supports subsequent clinical management.