Data sharing to improve concordance in variant interpretation across laboratories: results from the Canadian Open Genetics Repository

Abstract

BackgroundThis study aimed to identify and resolve discordant variant interpretations across clinical molecular genetic laboratories through the Canadian Open Genetics Repository (COGR), an online collaborative effort for variant sharing and interpretation.MethodsLaboratories uploaded variant data to the Franklin Genoox platform. Reports were issued to each laboratory, summarising variants where conflicting classifications with another laboratory were noted. Laboratories could then reassess variants to resolve discordances. Discordance was calculated using a five-tier model (pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), benign (B)), a three-tier model (LP/P are positive, VUS are inconclusive, LB/B are negative) and a two-tier model (LP/P are clinically actionable, VUS/LB/B are not). We compared the COGR classifications to automated classifications generated by Franklin.ResultsTwelve laboratories submitted classifications for 44 510 unique variants. 2419 variants (5.4%) were classified by two or more laboratories. From baseline to after reassessment, the number of discordant variants decreased from 833 (34.4% of variants reported by two or more laboratories) to 723 (29.9%) based on the five-tier model, 403 (16.7%) to 279 (11.5%) based on the three-tier model and 77 (3.2%) to 37 (1.5%) based on the two-tier model. Compared with the COGR classification, the automated Franklin classifications had 94.5% sensitivity and 96.6% specificity for identifying actionable (P or LP) variants.ConclusionsThe COGR provides a standardised mechanism for laboratories to identify discordant variant interpretations and reduce discordance in genetic test result delivery. Such quality assurance programmes are important as genetic testing is implemented more widely in clinical care.

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“…For this study, we considered variants classified as pathogenic, likely pathogenic or of uncertain significance (VUS). As reported in Mighton et al, 2022 [ 20 ], we considered synonymous variants which are not predicted to impact splicing (BP7) as likely benign. In addition, we defined as likely benign missense VUS variants that met the BP6 criterion (Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation) [ 21 ].…”

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“…[182][183][184][185][187][188][189] Strategies to generate evidence to reclassify VUS include family segregation studies, 190,191 functional studies, 192,193 and data sharing. 194,195 Variant reclassifications can affect patients' medical care. 182,185 It is important that laboratories periodically reassess variants to ensure patients receive up-to-date variant classifications to guide their medical management.…”

“…Data sharing between laboratories and through public databases such as ClinVar 197 is essential to improve consistency in variant interpretation. Data sharing efforts in the USA, 196,198,199 Canada, 194,195,200 and Norway 201 have been successful at reducing discordance in variant interpretation across clinical genetic diagnostic laboratories.…”

“…In particular, most reclassified VUS (eg, >90% 184,187 ) are downgraded to likely benign or benign 182–185,187–189 . Strategies to generate evidence to reclassify VUS include family segregation studies, 190,191 functional studies, 192,193 and data sharing 194,195 . Variant reclassifications can affect patients' medical care 182,185 .…”

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“…One of the more commonly mentioned platforms is Genoox, which offers a user customized pipeline handling everything from alignment and variant calling to diagnosis support provided by an AI engine named Franklin. The tool has been successfully used both for solving new cases and for periodic re-analysis [ 89 , 105 , 106 , 107 ] and is now introducing an integration with optical genome mapping data (Bionano, San Diego, CA, USA) to enable the analysis of structural variants [SVs].…”