Differences in patient ascertainment affect the use of gene-specified ACMG/AMP phenotype-related variant...

The American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for variant classification are widely used for clinical interpretation of gene test results. These guidelines may be specified to genes/syndromes of interest to improve their utility in the clinical setting. As part of these specifications, phenotype-related criteria can be detailed and weighted depending on the personal history of disease for a given variant carrier. We investigated how ascertainment can affect the significance and/or weight of patient phenotype as a predictor of germline-variant pathogenicity, using the Li-Fraumeni Syndrome gene TP53 as an example. Likelihood ratios in favor of variant pathogenicity were determined for a report of the personal history of several TP53-related cancers, using data from 2,656 probands undergoing single-gene testing (SGT) and 15,483 undergoing multi-gene panel testing (MGPT). Overall, TP53-associated cancers were more predictive of pathogenicity, and demonstrated greater evidence weight, in the MGPT versus SGT dataset. This observation is almost certainly explained by differences in proband ascertainment for the two streams of testing, and these findings have implications for germline-variant classification using ACMG/AMP guidelines.