Tailoring the American College of Medical Genetics and Genomics and the Association for Molecular Pathology Guidelines for the Interpretation of Sequenced Variants in the Gene for Marfan Syndrome: Proposal for a Disease- and Gene-Specific Guideline.

Background: The introduction of next-generation sequencing techniques has substantially increased the identification of new genetic variants and hence the necessity of accurate variant interpretation. In 2015, the American College of Medical Genetics and Genomics and the Association for Molecular Pathology proposed new variant interpretation guidelines. Gene-specific characteristics were, however, not considered, sometimes leading to inconsistent variant interpretation.

Methods: To allow a more uniform interpretation of variants in the (fibrillin-1) gene, causing Marfan syndrome, we tailored these guidelines to this gene and disease. We adapted 15 of the 28 general criteria and classified 713 variants previously identified in our laboratory as causal mutation or variant of uncertain significance according to these adapted guidelines. We then compared the agreement between previous methods and the adapted American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria.

Results: Agreement between the methods was 86.4% (K-alpha, 0.6). Application of the tailored guidelines resulted in an increased number of variants of uncertain significance (14.5% to 24.2%). Of the 85 variants that were downscaled to likely benign or variant of uncertain significance, 59.7% were missense variants outside a well-established functional site. Available clinical- or segregation data, necessary to further classify these types of variants, were in many cases insufficient to aid the classification.

Conclusions: Our study shows that classification of variants remains challenging and may change over time. Currently, a higher level of evidence is necessary to classify a variant as pathogenic. Gene-specific guidelines may be useful to allow a more precise and uniform interpretation of the variants to accurately support clinical decision-making.