NM_000051.4:c.8261C>T (p.Thr2754Ile) is a missense variant in ATM, a gene for which loss of function is an established mechanism of disease in ataxia-telangiectasia and in which germline variants confer susceptibility to breast, ovarian, and pancreatic cancer (ClinGen HBOP VCEP v1.5.0).¹ This variant is present at extremely low frequency in population databases: gnomAD v4.1 reports 4 heterozygous carriers among 1,605,254 alleles (total AF=2.49e-06; grpmax FAF=2.8e-07) with no homozygotes observed, and gnomAD v2.1 reports 1 heterozygous carrier among 31,352 alleles (AF=3.19e-05). It is absent from gnomAD-Canada v1.0.² In silico predictors are inconclusive: REVEL score is 0.633 (below the ATM VCEP PP3 threshold of >0.7333 but above the BP4 threshold of ≤0.249), BayesDel score is -0.0763065, and SpliceAI predicts no significant splice impact (max delta score = 0.01).³ This variant has been reported in ClinVar as Uncertain Significance by 6 clinical laboratories (ClinVar Variation ID: 127457), with no expert panel classifications available. No functional studies, case-control analyses, segregation data, or observations in trans with pathogenic ATM variants have been identified for this specific variant.⁴ The variant is absent from COSMIC (no somatic cancer reports) and does not fall within a statistically significant Cancer Hotspot. OncoKB reports no reviewed functional evidence and classifies this variant as having Unknown Oncogenic Effect.⁵ Under the ClinGen HBOP VCEP for ATM v1.5.0, only PM2_Supporting is met (allele frequency ≤0.001% in gnomAD v4). All other applicable criteria are either not met or not applicable. With a single supporting-level pathogenic criterion and no benign criteria met, the variant is classified as Uncertain Significance (VUS) per the ACMG/AMP 2015 combining rules as adopted by the ATM VCEP.⁶