This missense variant (c.8546G>C, p.Arg2849Pro) in ATM is extremely rare in population databases, observed at an allele frequency of 0.00012% in gnomAD v4.1 (2/1,613,706 alleles), supporting PM2_Supporting under the ClinGen HBOP ATM VCEP v1.5.0 specifications.

The REVEL in silico predictor yields a score of 0.919, exceeding the VCEP PP3 threshold of >0.733, and SpliceAI predicts no splicing impact (max delta 0.01), supporting PP3 at supporting strength.

Exploratory functional evidence from high-throughput assays (PMID 31097817, PMID 29650054) suggests the variant impairs ATM kinase activity, which may support PS3. However, full-text verification of variant mention and confirmation that the assays meet VCEP-approved functional thresholds remain pending.

The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has classified this variant as Likely Pathogenic (ClinVar variation ID 490737, review status: reviewed by expert panel). Seven clinical laboratories concur (6 Likely pathogenic, 1 Pathogenic).

Under the VCEP combination rules, the currently confirmed criteria (PM2_Supporting, PP3) yield 2 pathogenic supporting points, which is insufficient to reach Likely Pathogenic. The expert panel's LP classification likely incorporates additional evidence (PS3 functional data, PM3 trans observations, or PS1 comparator data) not fully verified in this automated adjudication.