For the requested consequence/LOF criteria, the ATM VCEP makes PVS1 inapplicable to this missense variant, PM4 applicable only to stop-loss variants, and BP3 not applicable. PS2, PM6, and BS4 are explicitly Not Applicable in the ATM VCEP v1.6 CSPEC. PP1 is not assessed because no qualifying affected-relative segregation or family testing data are documented. Within this requested group, PS4 is not assessed because the required case-control statistics are unavailable; PP4, PP5, BP5, and BP6 are not applicable under the ATM VCEP. No publications were reviewed because the case literature packet contains no PMIDs and none of these criteria requires a paper-specific finding once the VCEP applicability rules are applied. For this missense variant, PP3 is not met because neither the VCEP's REVEL nor SpliceAI damaging thresholds is reached; BP4 is met at supporting strength through REVEL <=.249; BP7 is not applicable by variant type. Population evidence supports PM2 at supporting strength; BA1 and BS1 are not met, and BS2 is not applicable under the ATM VCEP's incomplete-penetrance rule.
Final classification
Uncertain Significance - Conflicting Evidence
PM2BP4
ATM
c.1261T>A
p.Ser421Thr
missense · exon 10
Gene context
NCBI Gene ↗
OncoKB ↗
ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.
This variant
For the requested consequence/LOF criteria, the ATM VCEP makes PVS1 inapplicable to this missense variant, PM4 applicable only to stop-loss variants, and BP3 not applicable.
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.6 v1.6 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2
BP4
Uncertain Significance - Conflicting Evidence
ATM c.1261T>A
missense · exon 10
PM2 + BP4
→
Uncertain Significance - Conflicting Evidence
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
PM2
supporting
Pathogenic
Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, giving a highest observed subpopulation frequency of 0%, below the VCEP's ≤0.001% threshold.
ClinGen ATM VCEP v1.6 CSPEC PM2 rule: Frequency ≤0.001% in the gnomAD subpopulation with the highest frequency; PM2 is used at supporting strength.gnomAD v2.1: NM_000051.4:c.1261T>A absent; observed frequency 0 and no homozygotes reported.gnomAD v4.1: NM_000051.4:c.1261T>A absent; observed frequency 0 and no homozygotes reported.
BP4
supporting
Benign
Met at supporting strength: REVEL 0.085 is below the VCEP BP4 missense cutoff of <=0.249.
Case evidence for NM_000051.4:c.1261T>A / p.(Ser421Thr) / p.(S421T): REVEL score 0.085.Case evidence for NM_000051.4:c.1261T>A: SpliceAI maximum delta score 0.012, also below the VCEP no-predicted-impact cutoff of <=0.1.Sun et al. 2025, Supplementary Table S1, row c.1261T>A / S421T: REVEL 0.085; Classification Functional, Confidence High, DeepATM_predicted No. The row provides predictor corroboration but no pre-assigned BP4 code.
Assessed · not applied
· 3 not met · 7 not assessed
Pathogenic
PS1
Not assessed: no pathogenic same-amino-acid comparator was identified in ATM_PS1_1.6.pdf, although the assessed variant's SpliceAI maximum delta was 0.012.
PS3
Not assessed: Sun et al.
PS4
Not assessed: no case-control p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is available to test the VCEP threshold.
PM3
Not assessed: no affected A-T proband, phenotype classification, second pathogenic variant, or phase evidence is available to assign the VCEP's PM3 points.
PP1
Not assessed: no affected-relative segregation count or parental/family testing result is documented to meet the VCEP's 1-, 2-, or ≥3-relative thresholds.
PP3
Not met: REVEL 0.085 is below the >0.7333 PP3 threshold and SpliceAI max delta 0.012 is below the >=0.2 splice-impact threshold.
Benign
BA1
Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax filtering allele frequency above the VCEP's >0.5% threshold.
BS1
Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax filtering allele frequency above the VCEP's >0.05% threshold.
BS3
Not assessed: c.1261T>A was directly classified Functional, but the non-approved assay lacks VCEP calibration for assigning BS3 rescue evidence.
BP2
Not assessed: no unaffected adult, pathogenic co-occurring variant, or cis/trans or homozygous phase observation is available to assign the VCEP's BP2 points.
N/A · 16
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.085. BayesDel score = -0.497898.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Sun et al. 2025
Searched
c.1261T>Ap.Ser421Thrp.S421T
Found
Sun et al. Supplementary Table S1 reports ATM c.1261T>A (p.S421T) as Functional with High confidence and DeepATM_predicted=No, indicating that the classification derives from the underlying prime-editing saturation genome editing measurement rather than a DeepATM computational prediction.
Variant
✓ Names this variant — characterised directly
Applied to
→BP4
supporting
The exact row supplies corroborative REVEL 0.085, but no pre-assigned BP4 code.
108250726 T A c.1261T>A S421T exon_10 11 Missense 421 22 0.08285539 0.316805449764385 0.085 0.1124 0 -0.490727443558432 Functional High No
Location Supplementary Table S1, row 4039 in the converted full-text table · Context Table S1 reports combined function and eDA scores for ATM SNVs from a prime-editing saturation genome editing screen, with DeepATM_predicted distinguishing direct measurements from computational predictions. · full text
Sources & reference links