P31 UK guidance for analysis and reporting of ATM variants ascertained through cancer indications

Biallelic pathogenic variants in ATM cause ataxia-telangiectasia, while heterozygous carriers may have increased risks of certain cancers. Truncating variants and the recurrent missense variant c.7271T>G are associated with higher cancer risks, compared to other, non-truncating variants. Current risk models do not distinguish between variant types, and the survival benefit of risk-reducing interventions in carriers remains uncertain. Interpretation of missense variants imposes a disproportionate demand on laboratory resources relative to clinical utility. To optimise use of NHS capacity, the UK Cancer Genetics Group (UKCGG) and the Cancer Variant Interpretation Group–UK (CanVIG-UK) Steering and Advisory Group (CStAG) have developed guidance for ATM variant reporting under cancer indications. Diagnostic testing should be restricted to canonical protein-truncating variants and c.7271T>G. Targeted constitutional testing for additional variants ascertained under other indications may be considered where robust evidence supports loss of function, aberrant splicing, or a significant cancer association (odds ratio >2.0, lower confidence interval >1.5). Reports should clearly state evidentiary basis and highlight uncertainties regarding cancer risk and utility of cascade testing. As maintenance of a formal whitelist is not feasible, evidence should be submitted to the CanVar-UK database. This framework prioritises variants with the greatest clinical utility, supporting consistent and equitable genomic practice.