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ATMc.1261T>ANot classified
Print report
Variant interpretation report

ATM c.1261T>A, p.(Ser421Thr)

NM_000051.4:c.1261T>A NP_000042.3:p.(Ser421Thr) Missense · exon 10 View identifiers
Classification
Not classified

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. Select a step to read what it means.

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About ATM

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.

NCBI Gene ↗ OncoKB ↗
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.
01The reasoning

How it was classified

The recorded framework is ClinGen ATM VCEP v1.6. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met at supporting strength: REVEL 0.085 is below the VCEP BP4 missense cutoff of <=0.249.

Recorded classification: Not classified

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
REVEL score
0.085 recorded score

Recorded REVEL score: 0.085. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.6, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 7 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingVCEPMet 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. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PM2 only at supporting strength when the frequency is at most 0.001% in the gnomAD subpopulation with the highest frequency, with an exception for a single observation in one subpopulation. NM_000051.4:c.1261T>A is absent from gnomAD v2.1 and gnomAD v4.1, so the highest observed subpopulation frequency is 0%, which meets the threshold. The VCEP rule does not require substituting non-cancer subsets for the default all-comers gnomAD entries, and none is needed here because the variant is absent from both default datasets.

VCEP rule
Frequency **≤.001%** in gnomAD subpopulation with the highest frequency ... Exception: If >0.001% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2\_supporting would apply.
Evidence considered
  • 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.
  • The governing ATM VCEP text does not specify a non-cancer or exome-only source for PM2, so the default all-comers gnomAD entries were used; both default datasets independently report absence.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingVCEPMet at supporting strength: REVEL 0.085 is below the VCEP BP4 missense cutoff of <=0.249. Details ▾Hide ▴
Reasoning

This is a missense variant, and the VCEP BP4 missense path applies REVEL <=.249. The REVEL score is 0.085, which meets that benign-prediction threshold. SpliceAI also predicts no significant splice impact (maximum delta 0.012, <=0.1), but that result is corroborative only and is not counted as a separate BP4 application. The governing ATM Table S1 row also reports REVEL 0.085 and does not contain a pre-assigned BP4 code.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • 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.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Not met · 3 · evaluated, threshold not reached

PP3 VCEPNot 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. Details ▾Hide ▴
Reasoning

This is a missense variant, so the VCEP PP3 missense path requires REVEL >.7333, while its splicing path permits predicted splice impact by SpliceAI >=0.2 for missense variants. REVEL is 0.085 and SpliceAI max delta is 0.012, so neither named damaging-prediction path meets the VCEP threshold. The governing ATM Table S1 row for c.1261T>A (S421T) reports REVEL 0.085 and DeepATM_predicted=No, but it does not pre-assign PP3 and therefore does not override the VCEP PP3 thresholds.

VCEP rule
* Missense: REVEL **\>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • 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 DS_AG 0.004, DS_AL 0.001, DS_DG 0.011, DS_DL 0.012; maximum delta score 0.012.
  • Sun et al. 2025, Supplementary Table S1, row c.1261T>A / S421T: CADD.phred 22, boostDM_score 0.08285539, EVE_scores_ASM 0.316805449764385, REVEL 0.085, AlphaMissense 0.1124, Combined_score -0.490727443558432, Classification Functional, Confidence High, DeepATM_predicted No; this row was treated as corroborative predictor information and not as a pre-assigned PP3 code.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BA1 VCEPNot 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. Details ▾Hide ▴
Reasoning

The ATM VCEP assigns BA1 only when the gnomAD population maximum filtering allele frequency exceeds 0.5%. NM_000051.4:c.1261T>A is absent from gnomAD v2.1 and gnomAD v4.1, so no population frequency exceeding the BA1 threshold is observed.

VCEP rule
Grpmax Filtering AF **>.5%** in gnomAD
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BA1 rule: Grpmax Filtering AF >0.5% in gnomAD.
  • gnomAD v2.1: NM_000051.4:c.1261T>A absent; no allele frequency or population maximum filtering AF reported.
  • gnomAD v4.1: NM_000051.4:c.1261T>A absent; no allele frequency or population maximum filtering AF reported.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot 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. Details ▾Hide ▴
Reasoning

The ATM VCEP assigns BS1 only when the gnomAD population maximum filtering allele frequency exceeds 0.05%. NM_000051.4:c.1261T>A is absent from gnomAD v2.1 and gnomAD v4.1, so no population frequency exceeding the BS1 threshold is observed.

VCEP rule
Grpmax Filtering AF **>.05%** in gnomAD
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BS1 rule: Grpmax Filtering AF >0.05% in gnomAD.
  • gnomAD v2.1: NM_000051.4:c.1261T>A absent; no allele frequency or population maximum filtering AF reported.
  • gnomAD v4.1: NM_000051.4:c.1261T>A absent; no allele frequency or population maximum filtering AF reported.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 7 · no assessment recorded

PS1 VCEPNot 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. Details ▾Hide ▴
Reasoning

The ATM VCEP PS1 rule requires the same amino-acid change as a previously established pathogenic variant and, for missense changes, that splicing be ruled out for both alterations. The governing file ATM_PS1_1.6.pdf was searched for c.1261T>A, p.Ser421Thr, and p.S421T; no entry for this variant was found, and the available evidence does not identify a previously established pathogenic ATM variant with the same Ser421Thr substitution. SpliceAI predicts no significant splice impact for the assessed variant (maximum delta score 0.012), but without an identified pathogenic same-amino-acid comparator the PS1 rule cannot be completed.

VCEP rule
* Use for missense changes as long as splicing is ruled-out for both alterations.  * Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.
Evidence considered
  • ATM_PS1_1.6.pdf: searches for c.1261T>A, p.Ser421Thr, and p.S421T returned no variant entry.
  • Variant normalization: NM_000051.4:c.1261T>A produces NP_000042.3:p.(Ser421Thr) / p.(S421T), a missense change.
  • SpliceAI result for NM_000051.4:c.1261T>A: DS_AG 0.004, DS_AL 0.001, DS_DG 0.011, DS_DL 0.012; maximum delta score 0.012.
Still missing
  • No entry for c.1261T>A, p.Ser421Thr, or p.S421T was found when ATM_PS1_1.6.pdf was searched; a previously established pathogenic same-amino-acid comparator is still required.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗spliceai ↗
PS3 VCEPNot assessed: Sun et al. directly measured c.1261T>A as Functional, but this assay is not among the VCEP-approved assays and cannot be calibrated to PS3 automatically. Details ▾Hide ▴
Reasoning

The governing ATM v1.6 rule permits PS3 only when the variant fails to rescue an ATM-specific feature, with Supporting strength for an ATM-specific feature alone and Moderate strength only when both an ATM-specific feature and radiosensitivity fail. Table S1 of Sun et al. 2025 contains an exact c.1261T>A row with Classification=Functional, Confidence=High, and DeepATM_predicted=No, indicating a directly measured prime-editing result rather than a computational extrapolation. However, the ClinGen HBOP approved-assay table searched for c.1261T>A, p.Ser421Thr, and p.S421T contains no variant-specific entry and lists only the approved Mitui, Barone, and Scott assay papers; the Sun et al. prime-editing assay is not one of those named approved assays. Therefore the available functional result cannot be assigned PS3 strength under the VCEP without human confirmation that this newer assay is acceptable and that its Functional classification maps to failure of an ATM-specific feature under the v1.6 calibration.

VCEP rule
Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. ... Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency
Evidence considered
  • Suppl_TableS1_PMID 40580951.xlsx, Table S1, row for c.1261T>A / S421T: Combined_score=-0.490727443558432, Classification=Functional, Confidence=High, DeepATM_predicted=No; the row is a direct prime-editing screen result rather than a DeepATM computational prediction.
  • clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx, sheets ATM kinase activity and ATM radiosensitivity: the approved assay papers are Mitui 2009 (PMID:18634022), Barone 2009 (PMID:19431188), and Scott 2002 (PMID:11805335); no row for c.1261T>A, p.Ser421Thr, or p.S421T is present.
  • The ATM v1.6 PS3 rule is rescue-based: failure of an ATM-specific feature alone is Supporting, while failure of both an ATM-specific feature and radiosensitivity is Moderate; the VCEP prohibits Strong PS3.
Still missing
  • No c.1261T>A, p.Ser421Thr, or p.S421T entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt, the VCEP-approved functional-assay calibration file.
  • No evidence was found that c.1261T>A was tested in the three VCEP-approved assay papers (PMID:18634022, PMID:19431188, or PMID:11805335).
  • Human review is required to determine whether the directly measured Sun et al. 2025 prime-editing result can be used under the ATM v1.6 PS3 specification and how its Functional classification corresponds to the VCEP's rescue-based rule.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PS4 VCEPNot assessed: no case-control p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is available to test the VCEP threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP makes PS4 applicable at Strong strength when a case-control study has p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥2 or a lower 95% confidence interval ≥1.5. The available evidence contains no case-control p-value, effect estimate, or lower 95% confidence interval for NM_000051.4:c.1261T>A, so the rule cannot be evaluated.

VCEP rule
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥2 **or** lower 95% CI ≥1.5).
Evidence considered
  • No case-control study p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval for NM_000051.4:c.1261T>A is present in the available case evidence.
  • The VCEP rule requires p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% confidence interval ≥1.5); no numeric comparison can be performed.
Still missing
  • A case-control study with its p-value and odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is required.
Sources
cspec ↗
PM3 VCEPNot assessed: no affected A-T proband, phenotype classification, second pathogenic variant, or phase evidence is available to assign the VCEP's PM3 points. Details ▾Hide ▴
Reasoning

The ATM VCEP PM3 rule requires a recessive-disease observation of the variant in trans with a pathogenic variant, with points assigned according to the affected A-T proband phenotype and phase. The case evidence bundle contains no affected-proband observation, phenotype classification, second-variant identity, or phase information for NM_000051.4:c.1261T>A (p.Ser421Thr; p.S421T). The governing ATM_PM3_BP2_1.6.pdf was searched for c.1261T>A, p.Ser421Thr, and p.S421T; no variant-specific entry was found. Therefore PM3 cannot be assigned from the available evidence.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, PM3 section: the VCEP defines PM3 for recessive disorders as the variant being detected in trans with a pathogenic variant.
  • ATM_PM3_BP2_1.6.pdf, Ataxia Telangiectasia PM3/BP2 table: affected A-T probands receive PM3 points based on phenotype confidence and whether the other variant is confirmed in trans, phase unknown, unidentified/VUS, or homozygous.
  • The case evidence bundle contains no affected-proband, A-T phenotype, second-variant, or phase observation for this variant.
  • ATM_PM3_BP2_1.6.pdf was searched for c.1261T>A, p.Ser421Thr, and p.S421T; no variant-specific entry was found.
Still missing
  • No affected A-T proband observation or confident/consistent phenotype classification is available.
  • No pathogenic or likely pathogenic ATM variant in trans, or phase-unknown second-variant record, is available.
  • No variant-specific entry for c.1261T>A, p.Ser421Thr, or p.S421T was found in ATM_PM3_BP2_1.6.pdf after searching all three notations.
Sources
vcep_atm_pm3_bp2_1_6 ↗
PP1 VCEPNot assessed: no affected-relative segregation count or parental/family testing result is documented to meet the VCEP's 1-, 2-, or ≥3-relative thresholds. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 PP1 rule assigns supporting, moderate, or strong evidence according to segregation in 1, 2, or at least 3 affected relatives, respectively. The case evidence contains no documented affected relatives, parental testing, meioses, or family segregation observations for NM_000051.4:c.1261T>A, so PP1 cannot be assigned.

VCEP rule
AR Condition: Segregation in ≥3 affected relatives ... AR Condition: Segregation in 2 affected relatives ... AR Condition: Segregation in 1 affected relative
Evidence considered
  • The consolidated case evidence reports no literature PMIDs and no documented proband, parental, meiosis, segregation, or non-segregation observations for NM_000051.4:c.1261T>A.
  • ClinGen ATM VCEP v1.6 PP1 rule: segregation in ≥3 affected relatives is strong, in 2 affected relatives is moderate, and in 1 affected relative is supporting.
Still missing
  • Documented segregation data are needed: number of affected relatives carrying the variant, with phenotype and relationship, and parental testing or phase where relevant.
Sources
cspec ↗
BS3 VCEPNot assessed: c.1261T>A was directly classified Functional, but the non-approved assay lacks VCEP calibration for assigning BS3 rescue evidence. Details ▾Hide ▴
Reasoning

The governing ATM v1.6 rule permits BS3 when a variant rescues an ATM-specific feature or radiosensitivity at Supporting strength, and when it rescues both at Moderate strength. Table S1 of Sun et al. 2025 contains an exact c.1261T>A row with Classification=Functional, Confidence=High, and DeepATM_predicted=No, but this result is from a prime-editing assay not listed among the VCEP's approved Mitui, Barone, and Scott assays. The result points toward preserved function, but the VCEP provides no calibration that converts this newer Functional classification into rescue of an ATM-specific feature or radiosensitivity. Accordingly, BS3 cannot be assigned without human review of assay acceptability and readout equivalence under ATM v1.6.

VCEP rule
Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. ... Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Evidence considered
  • Suppl_TableS1_PMID 40580951.xlsx, Table S1, row for c.1261T>A / S421T: Combined_score=-0.490727443558432, Classification=Functional, Confidence=High, DeepATM_predicted=No; this is direct prime-editing measurement, not a model-only prediction.
  • clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx, sheets ATM kinase activity and ATM radiosensitivity: the VCEP calibration covers approved assay methods and does not contain a variant-specific row for c.1261T>A, p.Ser421Thr, or p.S421T.
  • The ATM v1.6 BS3 rule requires rescue of either an ATM-specific feature or radiosensitivity for Supporting, or both for Moderate.
Still missing
  • No c.1261T>A, p.Ser421Thr, or p.S421T entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt, the VCEP-approved functional-assay calibration file.
  • No approved-assay result was identified for c.1261T>A in Mitui 2009, Barone 2009, or Scott 2002.
  • Human review is required to determine whether Sun et al. 2025's Functional classification demonstrates rescue of an ATM-specific feature, radiosensitivity, or both under the VCEP's BS3 rule.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP2 VCEPNot assessed: no unaffected adult, pathogenic co-occurring variant, or cis/trans or homozygous phase observation is available to assign the VCEP's BP2 points. Details ▾Hide ▴
Reasoning

The ATM VCEP BP2 rule requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder or observation in cis with a pathogenic variant in any inheritance pattern; its ATM table separately assigns negative points for an unaffected non-A-T adult proband with a pathogenic or likely pathogenic variant in trans or homozygously. The case evidence bundle contains no unaffected adult proband, cis/trans phase, homozygous observation, or pathogenic/likely pathogenic co-occurring variant for NM_000051.4:c.1261T>A. The governing ATM_PM3_BP2_1.6.pdf was searched for c.1261T>A, p.Ser421Thr, and p.S421T; no variant-specific entry was found. Therefore BP2 cannot be assigned from the available evidence.

VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, BP2 section: the VCEP defines BP2 as observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
  • ATM_PM3_BP2_1.6.pdf, Ataxia Telangiectasia PM3/BP2 table: BP2 negative points require an unaffected non-A-T adult proband and a pathogenic or likely pathogenic variant in the patient, with confirmed-in-trans, phase-unknown, or homozygous categories.
  • The case evidence bundle contains no unaffected adult, co-occurring pathogenic variant, phase, or homozygous observation for this variant.
  • ATM_PM3_BP2_1.6.pdf was searched for c.1261T>A, p.Ser421Thr, and p.S421T; no variant-specific entry was found.
Still missing
  • No unaffected non-A-T adult proband observation is available.
  • No pathogenic or likely pathogenic co-occurring variant and no cis, trans, or homozygous phase information is available.
  • No variant-specific entry for c.1261T>A, p.Ser421Thr, or p.S421T was found in ATM_PM3_BP2_1.6.pdf after searching all three notations.
Sources
vcep_atm_pm3_bp2_1_6 ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.1261T>A is a missense p.Ser421Thr substitution, not one of the ATM VCEP-defined null variant classes eligible for PVS1. Details ▾Hide ▴
Reasoning

PVS1 is not applicable because NM_000051.4:c.1261T>A produces the missense substitution p.(Ser421Thr) in exon 10, whereas the ATM VCEP rule limits PVS1 to null variants; the variant is not nonsense, frameshift, a canonical splice-site variant, an initiation-codon variant, or a single- or multi-exon deletion.

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease
Evidence considered
  • Case consequence evidence: NM_000051.4:c.1261T>A is a missense variant producing NP_000042.3:p.(Ser421Thr) / p.(S421T) in exon 10.
  • ATM_PVS1_1.6.pdf, page 1: the governing PVS1 definition lists nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, and single- or multi-exon deletion variants; it does not include missense substitutions.
Still missing
  • No entry for c.1261T>A, p.Ser421Thr, or p.S421T was found in ATM_PVS1_1.6.pdf.txt; this file is a general decision guide rather than a per-variant table.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗
PS2 VCEPNot applicable: the ATM VCEP v1.6 specification explicitly marks PS2 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC marks PS2 as Not Applicable; therefore de novo evidence is not evaluated for this variant under the governing specification.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC criterion entry for PS2: applicability is "Not Applicable".
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP states that benign and pathogenic variants occur within the same domains and germline hotspots are not well defined. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly makes PM1 not applicable because benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined. The case's domain_tables object is empty, but no domain reassessment can override the VCEP's explicit applicability decision.

VCEP rule
Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time
Evidence considered
  • ATM VCEP PM1 applicability: Not applicable.
  • ATM VCEP instruction: Do not use because benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined.
Sources
cspec ↗
PM4 N/ANot applicable: p.Ser421Thr is a missense substitution, whereas the ATM VCEP limits PM4 to stop-loss variants. Details ▾Hide ▴
Reasoning

PM4 is not applicable because the ATM VCEP specifies PM4 for stop-loss variants, while NM_000051.4:c.1261T>A is a missense p.(Ser421Thr) substitution and does not alter a termination codon or protein length.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • Case consequence evidence: NM_000051.4:c.1261T>A is a missense variant producing p.(Ser421Thr), with no stop-loss or protein-length change.
  • ATM VCEP v1.6 CSPEC PM4 entry: the specified use is for stop-loss variants.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 is limited to qualifying NMD-prone truncating variants, whereas this variant is missense p.Ser421Thr. Details ▾Hide ▴
Reasoning

The ATM VCEP PM5 rule is restricted to NMD-prone truncating variants receiving PVS1 Very Strong, or observed NMD-prone truncating splice variants receiving PVS1(RNA) Very Strong, with premature termination codons upstream of p.Leu3048. This assessed variant is a missense substitution at p.Ser421Thr, so it lies outside the variant types named by the governing PM5 rule.

VCEP rule
* DNA Variants: Apply to all NMD-prone, truncating variants receiving PVS1 (must be at VeryStrong) with premature termination codons upstream of p.Leu3048 * Splice Variants: Apply only to observed (not predicted) NMD-prone, truncating variants receiving PVS1(RNA) (must be at VeryStrong with high-quality RNA data) with premature termination codons upstream of p.Leu3048. This is not applicable for predicted splice impact without RNA data or PVS1(RNA) at reduced strength.
Evidence considered
  • ATM VCEP PM5 rule: DNA variants must be NMD-prone truncating variants receiving PVS1 Very Strong with premature termination codons upstream of p.Leu3048; the splice path requires observed RNA data and PVS1(RNA) Very Strong.
  • Variant consequence: NM_000051.4:c.1261T>A is missense and produces p.(Ser421Thr).
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP v1.6 specification explicitly marks PM6 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC marks PM6 as Not Applicable; therefore presumed de novo evidence is not evaluated for this variant under the governing specification.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC criterion entry for PM6: applicability is "Not Applicable".
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP states that ATM does not have a defined low rate of benign missense variation. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP2 not applicable and instructs that it should not be used because ATM does not have a defined low rate of benign missense variation. Therefore no PP2 evidence is assigned to this missense variant.

VCEP rule
Do not use: ATM does not have a defined low rate of missense benign variation.
Evidence considered
  • ATM VCEP PP2 applicability: Not applicable.
  • ATM VCEP instruction: Do not use because ATM does not have a defined low rate of missense benign variation.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for ATM breast cancer and incorporates ataxia-telangiectasia phenotype evidence into PM3/BP2. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP4 not applicable. For autosomal dominant ATM-related breast cancer, the VCEP states not to use PP4 because breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes; for autosomal recessive ataxia-telangiectasia, it is not a separate line of evidence because the phenotype evidence is built into the PM3/BP2 table.

VCEP rule
Autosomal Dominant: do not use as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3|BP2 table
Evidence considered
  • The VCEP marks PP4 as not applicable and provides separate exclusions for autosomal dominant breast cancer and autosomal recessive ataxia-telangiectasia.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP explicitly prohibits use of PP5 under the ClinGen VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP5 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The VCEP marks PP5 as not applicable for this VCEP.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP states that BS2 must not be used because ATM has incomplete penetrance. Details ▾Hide ▴
Reasoning

BS2 is not applicable under the ATM VCEP because ATM has incomplete penetrance; therefore, absence of disease in healthy individuals cannot be used for this criterion.

VCEP rule
Do not use: ATM has incomplete penetrance.
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BS2 applicability: Do not use; ATM has incomplete penetrance.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP v1.6 specification explicitly marks BS4 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC marks BS4 as Not Applicable; therefore non-segregation evidence is not evaluated for this variant under the governing specification.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC criterion entry for BS4: applicability is "Not Applicable".
Sources
cspec ↗
BP1 VCEPNot applicable: BP1 is excluded by the ATM VCEP because missense pathogenic variants are known for ATM. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP1 not applicable and specifically instructs not to use it because missense pathogenic variants are known for ATM. The assessed variant is missense, but the VCEP's applicability decision excludes BP1.

VCEP rule
Do not use: Missense pathogenic variants are known for ATM
Evidence considered
  • ATM VCEP BP1 applicability: Not applicable.
  • ATM VCEP instruction: Do not use because missense pathogenic variants are known for ATM.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP explicitly marks BP3 as not applicable for this framework. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the ATM VCEP specification, which explicitly marks this criterion as not applicable; the variant's missense consequence and exon 10 location do not create an exception to that governing applicability decision.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC BP3 entry: applicability is explicitly listed as Not Applicable.
Sources
cspec ↗
BP5 VCEPNot applicable: the VCEP prohibits BP5 because ATM variant co-occurrence does not reliably establish an alternate molecular basis for disease. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP5 not applicable and states not to use it because cases with multiple pathogenic variants have been observed without a noticeable difference in phenotype, while ATM's low penetrance makes co-occurrence with other pathogenic variants more frequent.

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
  • The VCEP marks BP5 as not applicable and instructs reviewers not to use it.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP explicitly prohibits use of BP6 under the ClinGen VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP6 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The VCEP marks BP6 as not applicable for this VCEP.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is limited to synonymous or deep intronic variants, whereas c.1261T>A is a missense substitution. Details ▾Hide ▴
Reasoning

The variant is a missense substitution in exon 10, not a synonymous or deep intronic variant. The VCEP BP7 rule is limited to synonymous and deep intronic variants, with a separate RNA-observation path for silent and intronic variants; therefore BP7 is outside its governing scope.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • Case variant consequence: missense, exon 10, NM_000051.4:c.1261T>A / NP_000042.3:p.(Ser421Thr).
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.1261T>A
Protein (HGVS p.)
NP_000042.3:p.(Ser421Thr)
GRCh38
chr11:108250726 T>A
GRCh37
chr11:108121453 T>A
Location and type
Exon 10 · missense

Gene diagram

Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.4. Select a row to find it on the plot.

ATMNM_000051.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -18 bp
0.001
SpliceAI acceptor gainat -25 bp
0.004
SpliceAI donor lossat +346 bp
0.012
SpliceAI donor gainat +27 bp
0.011

Other predictors

REVEL
0.085
BayesDel
-0.498

How the predictions were used

BP4 SupportingVCEPMet at supporting strength: REVEL 0.085 is below the VCEP BP4 missense cutoff of <=0.249. Details ▾Hide ▴
Reasoning

This is a missense variant, and the VCEP BP4 missense path applies REVEL <=.249. The REVEL score is 0.085, which meets that benign-prediction threshold. SpliceAI also predicts no significant splice impact (maximum delta 0.012, <=0.1), but that result is corroborative only and is not counted as a separate BP4 application. The governing ATM Table S1 row also reports REVEL 0.085 and does not contain a pre-assigned BP4 code.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • 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.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP3 VCEPNot 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. Details ▾Hide ▴
Reasoning

This is a missense variant, so the VCEP PP3 missense path requires REVEL >.7333, while its splicing path permits predicted splice impact by SpliceAI >=0.2 for missense variants. REVEL is 0.085 and SpliceAI max delta is 0.012, so neither named damaging-prediction path meets the VCEP threshold. The governing ATM Table S1 row for c.1261T>A (S421T) reports REVEL 0.085 and DeepATM_predicted=No, but it does not pre-assign PP3 and therefore does not override the VCEP PP3 thresholds.

VCEP rule
* Missense: REVEL **\>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • 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 DS_AG 0.004, DS_AL 0.001, DS_DG 0.011, DS_DL 0.012; maximum delta score 0.012.
  • Sun et al. 2025, Supplementary Table S1, row c.1261T>A / S421T: CADD.phred 22, boostDM_score 0.08285539, EVE_scores_ASM 0.316805449764385, REVEL 0.085, AlphaMissense 0.1124, Combined_score -0.490727443558432, Classification Functional, Confidence High, DeepATM_predicted No; this row was treated as corroborative predictor information and not as a pre-assigned PP3 code.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 N/ANot applicable: BP7 is limited to synonymous or deep intronic variants, whereas c.1261T>A is a missense substitution. Details ▾Hide ▴
Reasoning

The variant is a missense substitution in exon 10, not a synonymous or deep intronic variant. The VCEP BP7 rule is limited to synonymous and deep intronic variants, with a separate RNA-observation path for silent and intronic variants; therefore BP7 is outside its governing scope.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • Case variant consequence: missense, exon 10, NM_000051.4:c.1261T>A / NP_000042.3:p.(Ser421Thr).
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.085. BayesDel score = -0.497898.

0 paper records listed. 1 cited in the classification.

Cited in the classification

  • Sun et al. 2025
    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.
    → BP4 · supporting Names this variant
    PMID 40580951 ↗
    Source detail
    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.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.012 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.