Reclassification of ATM Missense Variants of Uncertain Significance by Integrating Results from Systematic Functional Assays into an ACMG Points-Based Framework

ATM (88 FATKIN domain missense VUS, reclassification)

Phospho-flow pKAP1 functional assay (100% specificity, 97% sensitivity) calibrated on 48 P/LP/benign controls → characterization of 88 ATM VUS → integration into ACMG points-based framework → reclassification of 90% of VUS

Development and application of a functional assay (phospho-flow pKAP1) to characterize 88 ATM missense VUS in the FATKIN domain. The assay achieves 100% specificity and 97% sensitivity calibrated on 48 pathogenic/benign controls. Of the 88 VUS, 79 (90%) were reclassified as pathogenic/likely pathogenic or benign/likely benign by integrating functional results into the ACMG points-based framework. Clinical validation on a cohort of 1,134 breast cancer patients confirms the distinction between neutral and deleterious variants.

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

This study represents a major advance for ATM, a moderate-penetrance gene often difficult to classify. Reclassification of 90% of missense VUS considerably reduces diagnostic uncertainty. Clinically, this directly impacts recommendations for intensive breast surveillance (annual MRI) and eligibility for PARP inhibitors. To be integrated into institutional ATM classification processes.

reclassification of actionable VUS +3; clinical validation n=1,134 +2; direct clinical impact (surveillance, PARP-i) +2; robust functional assay +1; Clin Cancer Res +1