Genetic variant interpretation in tumours in the French national ring trials Gen&Tiss - main criteria of improvement.

Cancer progression is driven by the accumulation of genetic variants, with technological advances increasing their detection. Precise variant interpretation is essential for clinical decision-making, necessitating robust quality assurance programmes. However, variability in interpretation can influence clinical outcomes. This study examines factors contributing to interpretation variability across French laboratories and evaluates the role of EQA schemes in enhancing consistency. Five-year data from the Gen&Tiss EQA programme (2018-2023) focusing on pathogenicity and actionability was analysed. Forty-four participants evaluated 75 variants in colon, lung, and melanoma cancer, while 17 evaluated 50 variants in ovarian cancer. The criteria included the entity responsible for post-analysis, MTB consultations, access to the private French OncoGenetics (FrOG) germline variant database, laboratory activity levels, type of institution, and interpretation complexity. Over the study period, laboratory performance improved significantly, with annual increases of 2.6% in multiparametric pathogenicity and 6.3% in actionability. Laboratories with dedicated somatic genetics services achieved the highest pathogenicity scores. While MTB consultations had inconsistent effects on variant interpretation, access to FrOG database was associated with higher pathogenicity scores in the ovarian programme. Additionally, higher laboratory activity correlated with improved interpretation accuracy, and increased interpretation complexity was linked to lower pathogenicity scores. These findings highlight structural factors affecting interpretation, but further investigation is needed at the individual level to inform policy and training strategies.