Shariant platform: Enabling evidence sharing across Australian clinical genetic-testing laboratories to support variant interpretation

Abstract

Sharing genomic variant interpretations across laboratories promotes consistency in variant assertions. A landscape analysis of Australian clinical genetic-testing laboratories in 2017 identified that, despite the national-accreditation-body recommendations encouraging laboratories to submit genotypic data to clinical databases, fewer than 300 variants had been shared to the ClinVar public database. Consultations with Australian laboratories identified resource constraints limiting routine application of manual processes, consent issues, and differences in interpretation systems as barriers to sharing. This information was used to define key needs and solutions required to enable national sharing of variant interpretations. The Shariant platform, using both the GRCh37 and GRCh38 genome builds, was developed to enable ongoing sharing of variant interpretations and associated evidence between Australian clinical genetic-testing laboratories. Where possible, two-way automated sharing was implemented so that disruption to laboratory workflows would be minimized. Terms of use were developed through consultation and currently restrict access to Australian clinical genetic-testing laboratories. Shariant was designed to store and compare structured evidence, to promote and record resolution of inter-laboratory classification discrepancies, and to streamline the submission of variant assertions to ClinVar. As of December 2021, more than 14,000 largely prospectively curated variant records from 11 participating laboratories have been shared. Discrepant classifications have been identified for 11% (28/260) of variants submitted by more than one laboratory. We have demonstrated that co-design with clinical laboratories is vital to developing and implementing a national variant-interpretation sharing effort. This approach has improved inter-laboratory concordance and enabled opportunities to standardize interpretation practices.

Figure 1

Overview of Shariant features Main features of Shariant include two-way sharing via an application programming interface (API); sharing of structured evidence and expertise against guidelines from the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP); discrepancy resolution; submission to international databases, including ClinVar; and controlled access.

Figure 2

Comparison of structured evidence between variant records (A) Example comparison of ACMG/AMP criteria applied by two laboratories. Red highlighting indicates a difference in the application of ACMG/AMP codes. (B) Example comparison of citations referenced for the same variant. Ticks indicate the referencing of a citation by a particular laboratory, and gray highlighting indicates a difference between laboratories.

Figure 3

Variants shared via Shariant over time (A) Submission and sharing of unique variants per laboratory, presented as totals per organization over time (mm-dd-yy). Frequency of upload is dependent on the interpretation system in use by a laboratory (lab). The spike in submissions in November 2021 was due to the recent onboarding of organization 6. Organization 6 has only submitted one large batch of records, and this batch included historical data. (B) Overall submissions of unique variants to Shariant over time and breakdown of variants submitted by one laboratory compared to variants submitted by multiple laboratories. (C) Unique variants contributed by more than one laboratory with breakdown of comparison category: concordant-agreement variants, concordant-confidence variants, and discrepant variants. As of December 2021, concordant-agreement variants (n = 211) included those that were pathogenic, n = 145 (69%); likely pathogenic, n = 19 (9%); VUS, n = 37 (18%); likely benign, n = 9 (4%); and benign, n = 1 (0.5%). Concordant-confidence variants (n = 31) included those that were pathogenic or likely pathogenic, n = 30 (97%); and benign or likely benign, n = 1 (3%). Discrepant variants are detailed in Table 3.

Figure 4

Reclassification of variants in Shariant Number of unique variants that were reclassified from August 2019 to December 2021. Initial classification is represented on the x axis, and the number of each pathogenicity for reclassified variants is displayed via the colored bars. Most variants that changed classification were initially VUS (n = 73; 72%), and the majority of these resolved to likely pathogenic or pathogenic (n = 54, 74% of this subgroup).

Figure 5

Genes with the most variants of uncertain significance across the context of hereditary cancer versus other diseases Results are shown for hereditary cancer (A) and other diseases (B). Variant records that were not matched to a variant or had no ACMG/AMP criteria assigned were removed, and only the most recently curated record was included if more than one variant record for a variant had been submitted by the same laboratory. All records that had a strength assigned for BS3 or PS3 were also excluded. Results for the hereditary cancer genes were driven by one laboratory.