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).

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.

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).

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.

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.

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.