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.

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.

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).

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).

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.

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.