NM_000051.4(ATM):c.8155C>T (p.Arg2719Cys) is a missense variant in exon 56 of ATM, a gene in which loss of function is an established mechanism for ataxia-telangiectasia (autosomal recessive) and in which pathogenic variants confer moderate risk for hereditary breast, ovarian, and pancreatic cancer.¹ This variant is present in gnomAD v4.1 at an overall allele frequency of 1.24e-05 (20/1,611,848 alleles; 0 homozygotes) with a grpmax filtering allele frequency of 9.55e-06. The allele frequency slightly exceeds the ATM VCEP PM2_Supporting threshold of ≤0.001%, and no subpopulation has a singleton observation.² In silico predictors are inconclusive: REVEL score is 0.613 (intermediate, not meeting PP3 threshold of >0.7333 nor BP4 threshold of ≤0.249). BayesDel score is -0.091 (weakly favoring benign). SpliceAI predicts no splicing impact (max delta = 0.03).³ A comprehensive functional screen of all ATM SNVs by Lee et al. (2025, PMID:40580951, Cell) using saturation prime editing classified p.Arg2719Cys as 'Functional' with 'High' confidence in a PARP inhibitor (olaparib) fitness assay, indicating the variant retains ATM DNA damage response function. Per ATM VCEP v1.5.0, this supports BS3_Supporting (variant rescues an ATM-specific feature).⁴ This variant has been reported in ClinVar as Uncertain Significance by 14 clinical laboratories (Variation ID: 185832). No expert panel classification is available. Three ClinVar submissions with criterion-level data (Ambry Genetics, Invitae, Color Health) also classify the variant as Uncertain Significance.⁵ This variant has been observed in somatic cancers (COSMIC COSV53736920, n=7), but somatic occurrence does not independently inform germline classification under the ATM VCEP framework. No evidence was found for: a pathogenic missense variant at the same residue (PS1), case-control enrichment (PS4), compound heterozygosity with a pathogenic variant in an A-T patient (PM3), cosegregation with disease (PP1), or observation in trans with a pathogenic variant in an unaffected individual (BP2). Applying the ATM VCEP v1.5.0 criteria, BS3_Supporting is the only criterion met. All pathogenic criteria are either not met or not applicable. Under the ACMG/AMP 2015 combining rules (adopted by the VCEP), one supporting benign criterion without any pathogenic criteria results in an overall classification of Uncertain Significance.⁶