Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK).

Garrett, A.; Allen, S.; Durkie, M.; Burghel, GJ.; Robinson, R.; Callaway, A.; Field, J.; Frugtniet, B.; Palmer-Smith, S.; Grant, J.; Pagan, J.; McDevitt, T.; Rowlands, CF.; McVeigh, T.; Hanson, H.; Turnbull, C.

Classification of variants of reduced penetrance in high-penetrance cancer susceptibility genes: Framework for genetics clinicians and clinical scientists by CanVIG-UK (Cancer Variant Interpretation Group-UK).

All Authors

Garrett, A.

Allen, S.

Durkie, M.

Burghel, GJ.

Robinson, R.

Callaway, A.

Field, J.

Frugtniet, B.

Palmer-Smith, S.

Grant, J.

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LTHT Author

Robinson, Rachel

LTHT Department

DNA Laboratory
Pathology

Non Medic

Clinical Scientist

Publication Date

2025

Item Type

Journal Article

Abstract

PURPOSE: Current practice is to report and manage likely pathogenic/pathogenic variants in a given cancer susceptibility gene as though having equivalent penetrance, despite increasing evidence of intervariant variability in risk associations. Using existing variant interpretation approaches, largely based on full-penetrance models, variants in which reduced penetrance is suspected may be classified inconsistently and/or as variants of uncertain significance. 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 working group. RESULTS: CanVIG-UK recommendations for amendment of the 2015 ACMG/AMP variant interpretation framework were developed for variants in which (A) active evidence suggests a reduced-penetrance effect size (eg, from case-control or segregation data) and (B) reduced penetrance effect is inferred from weaker/potentially inconsistent observed data. CONCLUSION: CanVIG-UK propose a framework for the classification of variants of reduced penetrance in high-penetrance genes. These principles, although developed for cancer susceptibility genes, are potentially applicable to other clinical contexts.