NM_000051.4:c.7357C>T (p.Arg2453Cys) is a missense variant in ATM exon 50, observed at very low frequency in population databases (gnomAD v4.1: 26/1,614,000 alleles, AF = 0.00161%; gnomAD v2.1: 3/251,250 alleles, AF = 0.00119%).¹ The variant meets PM2_supporting per the ClinGen HBOP VCEP v1.5.0 fallback rule: although global gnomAD v4 frequency (0.00161%) exceeds the primary threshold of ≤0.001%, the variant is observed at n=1 in the East Asian subpopulation, which is sufficiently rare to warrant supporting-level evidence for pathogenicity.² No pathogenic or likely pathogenic missense comparator at p.Arg2453 has been established (PS1 not met). REVEL score of 0.457 does not meet the VCEP PP3 threshold (>0.7333) or the BP4 threshold (≤0.249). SpliceAI predicts no splicing impact (max delta = 0.00).³ No variant-specific functional assay data (PS3/BS3) or segregation data (PP1) are available. The VCEP functional assay reference tables do not include this variant. The VCEP Suppl Table S1 (PMID 40580951) classifies the variant as 'Functional' with high confidence based on combined in silico scores, but computational predictions alone do not constitute experimental functional evidence sufficient for PS3.⁴ The variant has been reported in ClinVar as Uncertain Significance by 11 clinical laboratories (ClinVar Variation ID: 230366). No expert panel classification has been assigned. No peer-reviewed publication was identified that directly mentions NM_000051.4:c.7357C>T.⁵ The variant has been reported in COSMIC (COSV104592374, n=5) in somatic cancers, but this observation does not independently support germline pathogenicity classification under the HBOP VCEP framework. Applying the ClinGen HBOP VCEP v1.5.0 final classification rules (Richards et al. 2015 combining criteria), only PM2_supporting is met, with no benign criteria met. This does not reach the threshold for Likely Pathogenic (requires ≥2 supporting + ≥1 moderate, or ≥3 moderate, etc.) nor Likely Benign (requires ≥2 supporting benign). The variant is classified as Uncertain Significance.⁶