Purpose: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene (CSG) as though having equivalent penetrance, despite increasing evidence of inter-variant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants where reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance (VUS). We aimed to develop a national consensus approach for such variants within the Cancer Variant Interpretation Group UK (CanVIG-UK) multidisciplinary network. Methods: A series of surveys and live polls were conducted during and between CanVIG-UK monthly meetings on various scenarios potentially indicating reduced penetrance. These informed the iterative development of a framework for the classification of variants of reduced penetrance by the CanVIG-UK Steering and Advisory Group (CStAG) working group. Results: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants where (i) Active evidence suggests a reduced penetrance effect size (e.g. from case-control or segregation data) (ii) Reduced penetrance effect is inferred from weaker/potentially-inconsistent observed data. Conclusions: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, whilst developed for CSGs, are potentially applicable to other clinical contexts.

The authors have declared no competing interest.

A.G. and H.H. are supported by CRUK Catalyst award CanGene-CanVar [C61296/A27223]. S.A. and C.F.R. are supported by CG-MAVE, CRUK Programme Award [EDDPGM-Nov22/100004].

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