Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar

Abstract

Purpose: Data sharing through ClinVar offers a unique opportunity to identify interpretation differences between laboratories. As part of a ClinGen initiative, four clinical laboratories (Ambry, GeneDx, Partners Healthcare Laboratory for Molecular Medicine, and University of Chicago Genetic Services Laboratory) collaborated to identify the basis of interpretation differences and to investigate if data sharing and reassessment resolve interpretation differences by analyzing a subset of variants.

Methods: ClinVar variants with submissions from at least two of the four participating laboratories were compared. For a subset of identified differences, laboratories documented the basis for discordance, shared internal data, independently reassessed with the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines, and then compared interpretations.

Results: At least two of the participating laboratories interpreted 6,169 variants in ClinVar, of which 88.3% were initially concordant. Laboratories reassessed 242/724 initially discordant variants, of which 87.2% (211) were resolved by reassessment with current criteria and/or internal data sharing; 12.8% (31) of reassessed variants remained discordant owing to differences in the application of the ACMG-AMP guidelines.

Conclusion: Participating laboratories increased their overall concordance from 88.3 to 91.7%, indicating that sharing variant interpretations in ClinVar-thereby allowing identification of differences and motivation to resolve those differences-is critical to moving toward more consistent variant interpretations.Genet Med advance online publication 09 March 2017.

Figure 1. Distribution of variant interpretation comparisons between four clinical laboratories

(A) Interpretation comparison of data in ClinVar (as of January 1, 2016), pre-resolution efforts (B) Interpretation comparison after reassessing 33% (242/724) of shared variants with interpretation differences

Figure 2. Distribution of interpretation differences and resolution outcome per disease areas

Distribution of medically significant (P/LP vs VUS/LB/B) and other (VUS vs LB/B) differences within each disease area for all initial differences (“Total”), variants reassessed by laboratories (“Reassessed”), and final outcome for reassessed variants, including proportion resolved (“Outcome”).

Figure 3

Flowchart and outcome of variant resolution efforts.

Figure 4. Basis of initial interpretation differences for resolved variants

Over half of the initial interpretation differences were resolved simply because the re-interpretation had already been completed but was not yet submitted to ClinVar (17%, yellow shading) or by reassessing an old variant interpretation with the laboratory’s updated classification criteria, consistent with ACMG-AMP guidelines (36%, red shading). Differences in the use or weighting of public data accounted for 14% of interpretation differences (purple shading), including benign/likely benign thresholds (9%), and different data sources (5%). Differences in internal data accounted for 33% of interpretation differences (blue shading), including segregation data (10%), co-occurrence data (9%), internal proband frequency (8%), and detailed phenotype data (6%).