Yield of actionable variants from high-risk cancer gene panel testing in guideline-eligible and ineligible individuals.

Germline pathogenic or likely pathogenic variants in a multi-cancer panel of 29 clinically actionable genes

Many carriers of a germline cancer-predisposing pathogenic variant are not identified by testing criteria based on personal and family history. This retrospective cohort study analysed 153,767 unrelated consecutive women and men, unselected for personal or family cancer history, referred for genetic testing across multiple sites from June 2020 to August 2023. With a multi-cancer panel of 29 clinically actionable genes, pathogenic or likely pathogenic variants were identified in 6.5% of individuals meeting national testing criteria and 4.8% of those not meeting them. Overall, 22% of individuals with positive findings would have been missed had testing criteria been applied. Among individuals meeting only Lynch syndrome criteria, for example, positivity rates were 0.9% for MSH2 (versus 0.05% outside criteria) and 0.6% for MLH1 (versus 0.04%).

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The 22% figure of missed carriers argues for broader criteria, but it should be read with caution: a population "unselected for history" is still a population referred for testing, and thus already channelled by a prescriber. The abstract says nothing about the clinical outcome of carriers identified outside criteria, nor about the proportion of variants of uncertain significance reported. The argument echoes that of broad genomic approaches: the limit lies less and less in the technology and more and more in the criteria for access to testing.

Analysis by Dr Thibaut Benquey