The progression of the ClinGen gene clinical validity classification over timeMcGlaughon, Jennifer L.; Goldstein, Jennifer L.; Thaxton, Courtney; Hemphill, Sarah E.; Berg, Jonathan S.
doi: 10.1002/humu.23604pmid: 30311372
In order for ClinGen to maintain up‐to‐date gene‐disease clinical validity classifications for use by clinicians and clinical laboratories, an appropriate timeline for reevaluating curated gene‐disease associations will need to be determined. To provide guidance on how often a gene‐disease association should be recurated, a retrospective analysis of 30 gene curations was performed. Curations were simulated at one‐year intervals starting with the year of the first publication to assert disease‐causing variants in the gene to observe trends in the classification over time, as well as factors that influenced changes in classification. On average, gene‐disease associations spent the least amount of time in the “Moderate” classification before progressing to “Strong” or “Definitive.” In contrast, gene‐disease associations that spent five or more years in the “Limited” classification were most likely to remain “Limited” or become “Disputed/Refuted.” Large population datasets contributed to the reclassification of several gene‐disease associations from “Limited” to “Disputed/Refuted.” Finally, recent advancements in sequencing technology correlated with an increase in the quantity of case‐level evidence that was curated per paper. This study provided a number of key points to consider when determining how often to recurate a gene‐disease association.
On the verge of diagnosis: Detection, reporting, and investigation of de novo variants in novel genes identified by clinical sequencingThiffault, Isabelle; Cadieux‐Dion, Maxime; Farrow, Emily; Caylor, Raymond; Miller, Neil; Soden, Sarah; Saunders, Carol
doi: 10.1002/humu.23646pmid: 30311385
The variable evidence supporting gene–disease associations contributes to the difficulty of accurate variant reporting in a clinical setting. An evidence‐based scoring system for evaluating the clinical validity of gene–disease associations, proposed by ClinGen, considers experimental as well as genetic evidence. De novo variants are heavily weighted, given the overall rarity in the genome and their contribution to human disease, however they are reported as “genes of unknown significance” in our center when there is insufficient evidence for the gene–disease assertion. We report a collection of 21 de novo variants in genes of unknown clinical significance ascertained via clinical testing, of which eight of 21 (38%) are predicted to cause loss of function. These genes were subjected to ClinGen scoring to assess the strength of gene–disease relationships. Using a cutoff for moderate high or strong, 10 of 21 genes now have sufficient evidence to qualify as likely pathogenic or pathogenic variants. Sharing such cases with phenotypic data is imperative to strengthen available genetic evidence to ultimately upgrade clinical validity classifications and facilitate accurate molecular diagnosis.
Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterionAbou Tayoun, Ahmad N.; Pesaran, Tina; DiStefano, Marina T.; Oza, Andrea; Rehm, Heidi L.; Biesecker, Leslie G.; Harrison, Steven M.; ,
doi: 10.1002/humu.23626pmid: 30192042
The 2015 ACMG/AMP sequence variant interpretation guideline provided a framework for classifying variants based on several benign and pathogenic evidence criteria, including a pathogenic criterion (PVS1) for predicted loss of function variants. However, the guideline did not elaborate on specific considerations for the different types of loss of function variants, nor did it provide decision‐making pathways assimilating information about variant type, its location, or any additional evidence for the likelihood of a true null effect. Furthermore, this guideline did not take into account the relative strengths for each evidence type and the final outcome of their combinations with respect to PVS1 strength. Finally, criteria specifying the genes for which PVS1 can be applied are still missing. Here, as part of the ClinGen Sequence Variant Interpretation (SVI) Workgroup's goal of refining ACMG/AMP criteria, we provide recommendations for applying the PVS1 criterion using detailed guidance addressing the above‐mentioned gaps. Evaluation of the refined criterion by seven disease‐specific groups using heterogeneous types of loss of function variants (n = 56) showed 89% agreement with the new recommendation, while discrepancies in six variants (11%) were appropriately due to disease‐specific refinements. Our recommendations will facilitate consistent and accurate interpretation of predicted loss of function variants.
Updated recommendation for the benign stand‐alone ACMG/AMP criterionGhosh, Rajarshi; Harrison, Steven M.; Rehm, Heidi L.; Plon, Sharon E.; Biesecker, Leslie G.; ,
doi: 10.1002/humu.23642pmid: 30311383
The Clinical Genome Resource (ClinGen) Sequence Variant Interpretation Working Group set out to refine the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists (ACMG/AMP) variant pathogenicity recommendations for stand‐alone rule BA1 (a variant with minor allele frequency [MAF] > 0.05 is benign), by clarifying how it should be used and specifying a set of variants that should be exempted from this rule. We cross‐referenced ClinVar and Exome Aggregation Consortium data to identify variants for which there was a plausible argument for pathogenicity and the variant exists in one or more population data sets at MAF > 0.05. We identified nine such variants that were present in these data sets that may not be benign. The ACMG/AMP criteria were applied to these variants that resulted in four pathogenic and five variants of uncertain significance. We have refined benign rule BA1 by clarifying terms used to describe its use, which databases we recommend using, and assumptions made about this rule. We also recognized an initial list of nine variants for which there was some evidence of pathogenicity even though the MAF was high for these variants. We specify processes whereby individuals can petition ClinGen for amendments to our variant‐specific assertions and the criteria experts should use when setting a numerically lower threshold for BA1 for specific genes.
Quantifying the potential of functional evidence to reclassify variants of uncertain significance in the categorical and Bayesian interpretation frameworksBrnich, Sarah E.; Rivera‐Muñoz, Edgar A.; Berg, Jonathan S.
doi: 10.1002/humu.23609pmid: 30095857
Additional variant interpretation tools are required to effectively harness genomic sequencing for clinical applications. The American College of Medical Genetics and Genomics (ACMG) and Association for Molecular Pathology (AMP) published guidelines for clinical sequence variant interpretation, incorporating different types of data that lend varying levels of support towards a benign or pathogenic interpretation. Variants of uncertain significance (VUS) are those with either contradictory or insufficient evidence, and their uncertainty complicates patient counseling and management. Functional assays may provide a solution to evidence gaps relegating variants to the VUS category, but the impact of functional evidence in this framework has not been assessed. We employ an algorithmic analysis of the ACMG/AMP combining rules to assess how the availability of strong functional evidence could theoretically improve the ability to make a benign or pathogenic assertion. We follow this with analysis of actual evidence combinations met by variants through expert curations as part of the Clinical Genome Resource (ClinGen). We also examine the impact of functional evidence in a Bayesian adaptation of the ACMG/AMP framework. This lays the groundwork for an evidence‐based prioritization of assay development and variant assessment by identifying genes and variants that may benefit the most from functional data.