NM_000051.4:c.7381C>T (p.Arg2461Cys) is a missense variant in ATM, a gene where loss of function is an established mechanism for Ataxia-Telangiectasia (AR) and heterozygous variants confer moderate risk for breast and other cancers (AD). This variant is not a null variant and SpliceAI predicts no splicing impact (max delta 0.07); PVS1 is not applicable per the ATM VCEP v1.5.0 decision tree.¹ This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00613% (99/1,614,160 alleles; 0 homozygotes) with a grpmax filtering AF of 0.039%. The frequency exceeds the PM2_Supporting threshold (≤0.001%) but does not reach BS1 (>0.05%) or BA1 (>0.5%).² In silico predictions are inconclusive: REVEL score of 0.707 falls between the PP3 threshold (>0.7333) and BP4 missense threshold (≤0.249), neither meeting nor refuting pathogenicity. However, SpliceAI predicts no splicing impact (max delta 0.07 ≤ 0.1), satisfying BP4_Supporting.³ This variant has been reported in ClinVar (VCV000142541) with predominantly uncertain significance classifications (14 clinical laboratories), with a minority of likely benign (3) and benign (1) submissions. No expert panel classification is available.⁴ Functional evidence from the VCEP-validated Barone 2009 (PMID:19431188) kinase assay suggests partial impairment of ATM autophosphorylation, potentially supporting PS3_Supporting, but full-text verification of the variant-specific result was not possible in this assessment. Human review is recommended.⁵ No case-control study meeting PS4 criteria, no published segregation data for PP1, and no phased trans/cis data for PM3/BP2 were identified for this variant. Applying the ATM VCEP v1.5.0 criteria combination rules (Richards et al. 2015), only BP4_Supporting is met with no pathogenic criteria satisfied. The variant is classified as a Variant of Uncertain Significance (VUS). If PS3_Supporting is confirmed upon human review of the functional data, the variant would remain VUS (1 pathogenic supporting + 1 benign supporting under Rule31).⁶