Adopting High-Resolution Allele Frequencies Substantially Expedites Variant Interpretation in Genetic Diagnostic Laboratories

Publication date: Available online 25 April 2019Source: The Journal of Molecular DiagnosticsAuthor(s): Mahdi Ghani, Landry Nfonsam, Erinija Pranckeviciene, Hussein Daoud, Ryan Potter, Caitlin Chisholm, Patricia E. Harper, Audrey Schaffer, Leichelle Little, Elizabeth Sinclair-Bourque, Jean McGowan-Jordan, Amanda Smith, Lucas Bronicki, Olga JarinovaA cohort of 1,242 individuals tested in a clinical diagnostic laboratory was used to test whether the “Filtering Allele Frequencies” (FAFs)-based framework, recently recommended for MHY7-associated cardiomyopathy, is extendable to 45 cardiomyopathy genes. Statistical analysis revealed a threshold of 0.00164% for the extreme outlier allele frequencies (AFs), based on the gnomAD (exome fraction) total AFs of 138 unique pathogenic and likely pathogenic variants; 135 of which (97.8%) had AFs0.03%, frequencies above which were estimated here as strong evidence against pathogenicity. Interestingly, 74.5% (172/231) of the unique VUCSs with FAFs>0.03% had gnomAD popmax AFs>0.1%, deemed here as standalone evidence against pathogenicity. Accordingly, using a FAF threshold of>0.1%, compared to AF>1%, led us to issue considerably more (25.9% vs 41.3%) negative patient reports. Also, 82.7% (N=629) of the unique classified benign or likely benign variants with AFs 0.1% reinforcing the use of this filtering strategy. Together, these data demonstrate that implementing FAF thresholds may considerably decrease the amount of var...
Source: The Journal of Molecular Diagnostics - Category: Pathology Source Type: research

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PMID: 31609654 [PubMed - in process]
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