NM_000051.4:c.4247A>G (p.Gln1416Arg) is a rare missense variant in ATM with an allele frequency of 0.00087% in gnomAD v4.1 (14/1,604,866 alleles, 0 homozygotes), meeting PM2_Supporting under the ClinGen HBOP VCEP v1.5.0 threshold of ≤0.001%.

Computational predictors are inconclusive: REVEL score of 0.45 falls between the VCEP thresholds for PP3 (>0.7333) and BP4 (≤0.249), and BayesDel score of -0.0913068 is weakly benign. SpliceAI predicts no splicing impact (max delta=0.04). Neither PP3 nor BP4 is met.

This variant has been reported in ClinVar as Uncertain Significance by 6 clinical laboratories (ClinVar Variation ID: 230064, review status: criteria provided, single submitter). No expert panel classification has been recorded.

No variant-specific functional data (PS3/BS3), case-control studies (PS4), segregation data (PP1), or co-occurrence data (BP2) were identified for this variant. OncoKB reports Unknown Oncogenic Effect. The variant has not been reported in COSMIC.

With only PM2_Supporting met and no pathogenic moderate/strong/very strong criteria fulfilled, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP framework as specified by the ClinGen HBOP VCEP for ATM v1.5.0.