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ATMc.3077+1G>APathogenic
Print report
Variant interpretation report

ATM c.3077+1G>A, p.?

NM_000051.4:c.3077+1G>A NP_000042.3:p.? Canonical splice · intron 20 View identifiers
Classification
Pathogenic

Variant description:

The ATM NM_000051.4:c.3077+1G>A (NP_000042.3:p.?) splicing variant has previously been reported in somatic cancers (COSMIC; COSV109415800, n = 5 times). This variant is predicted to disrupt normal RNA processing, resulting in either an aberrant protein product or nonsense-mediated RNA decay. Experimental evidence: Direct prime-editing data classified c.3077+1G>A as Non-functional with High confidence and DeepATM_predicted=No. Based on available guidelines, this variant is considered to be Pathogenic.

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

Pathogenic.A pathogenic classification under the recorded framework.

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Met, very strong: the ATM VCEP pre-assigned list-A row for c.3077+1G>A specifies disrupted reading frame, predicted NMD, and full-strength PVS1.

PS3Supporting
PS3 · supporting

Met at Supporting: direct prime-editing data classified c.3077+1G>A as Non-functional with High confidence and DeepATM_predicted=No.

PM2Supporting
PM2 · supporting

Met at supporting: the highest gnomAD subpopulation frequency is 0.00008474834825469252%, below the VCEP's ≤0.001% PM2 threshold.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: PVS1 very strong plus PS3 and PM2 supporting satisfy the ATM VCEP Version 1.6 Rule4 combination.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
1 / 1,613,934 alleles

gnomAD v4.1: 1 / 1,613,934 alleles. Recorded AF 6.19604e-07. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250488 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16164 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.992 maximum delta

Recorded SpliceAI maximum delta score: 0.992. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions

4 Likely pathogenic · 1 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

Applied · PS3 → OncoKB ↗
Somatic evidence
5 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV109415800, n = 5 times).

Context only COSMIC ↗
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: 3 met · 4 not met · 5 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 criteria, the governing VCEP directly assigns full-strength PVS1 to the exact c.3077+1G>A variant; PM4 and BP3 are not applicable under the VCEP rules.

PS2, PM6, and BS4 are explicitly not applicable in the ClinGen HBOP ATM VCEP v1.6 specification.

PP1 cannot be assessed because no informative affected-relative segregation data are documented; no generic ACMG/AMP rule was substituted.

Only PP3, BP4, and BP7 were adjudicated. The canonical donor +1 location places PP3 outside its stated splice-prediction scope; BP4 is not met because SpliceAI max delta 0.992 is above the ≤0.1 no-impact threshold; BP7(RNA) is not assessed because no qualifying observed RNA result is available.

The exact governing Sun et al. 2025 Table S1 row for c.3077+1G>A was consulted and recorded, but its functional classification was not used as computational evidence or double-counted across criteria.

Met · 3

PVS1 Very strongVCEPMet, very strong: the ATM VCEP pre-assigned list-A row for c.3077+1G>A specifies disrupted reading frame, predicted NMD, and full-strength PVS1. Details ▾Hide ▴
Reasoning

NM_000051.4:c.3077+1G>A is a canonical donor +1 splice variant in ATM, with NP_000042.3:p.? and the affected exon assigned to the N-terminal HEAT-repeat region. The governing ATM PVS1 file contains an exact pre-assigned entry for c.3077+1G>A: list A, N-terminal HEAT repeats, reading frame disrupted, NMD predicted, with full-strength PVS1. The pre-assigned VCEP table entry governs the call; no downgrade applies.

VCEP rule
c.3077+1G>A -> PVS1 (list A; N-terminal HEAT repeats; reading frame disrupted, NMD predicted) = very strong
Evidence considered
  • ATM_PVS1_1.6.pdf, exact matching row: c.3077+1G>A -> PVS1 (list A; N-terminal HEAT repeats; reading frame disrupted, NMD predicted) = very strong.
  • Case consequence assessment: NM_000051.4:c.3077+1G>A, canonical splice donor (+1), affected exon 20 of 63, NP_000042.3:p.?.
  • The VCEP's exact per-variant pre-assigned code outranks independent exon-skipping calculations for this criterion.
Sources
vcep_atm_pvs1_1_6 ↗cspec ↗pvs1_variant_assessment
PS3 SupportingVCEPMet at Supporting: direct prime-editing data classified c.3077+1G>A as Non-functional with High confidence and DeepATM_predicted=No. Details ▾Hide ▴
Reasoning

The exact variant row in Sun et al. 2025 Supplementary Table S1 is c.3077+1G>A with Classification=Non-functional, Confidence=High, and DeepATM_predicted=No, indicating a direct prime-editing measurement rather than a computational prediction. Under the VCEP's file-specific rule, a directly assayed non-functional result supports PS3_Supporting. The approved ATM assay-methodology table was also searched for c.3077+1G>A and p.?; it is a calibration table rather than a per-variant results table and contains no entry for this variant, so no additional approved-assay weight is applied.

VCEP rule
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
  • Sun et al. 2025 Supplementary Table S1, row c.3077+1G>A: Classification=Non-functional; Confidence=High; DeepATM_predicted=No; the row is a direct prime-editing measurement under the file's PS3/BS3 curation rule.
  • The VCEP approved-assay calibration file, sheets ATM kinase activity and ATM radiosensitivity, was searched using c.3077+1G>A and p.?; it lists assay methodology and strength calibration but no current-variant result.
Still missing
  • The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.3077+1G>A and p.?; no entry for this variant was found, and the table does not itself provide variant-specific assay results.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
PM2 SupportingVCEPMet at supporting: the highest gnomAD subpopulation frequency is 0.00008474834825469252%, below the VCEP's ≤0.001% PM2 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PM2 at supporting strength when the frequency is ≤0.001% in the gnomAD subpopulation with the highest frequency. The highest observed subpopulation frequency is 8.474834825469252e-07 (0.00008474834825469252%) in gnomAD v4.1 European non-Finnish, with one allele among 1,179,964; gnomAD v2.1 has zero observed alleles in every reported subpopulation. No VCEP rule requires a non-cancer or exome-only subset for these criteria, so the default all-comers gnomAD entries are used.

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 HBOP ATM VCEP v1.6 CSPEC PM2 rule: Frequency ≤0.001% in gnomAD subpopulation with the highest frequency; the VCEP assigns PM2 only as supporting evidence.
  • gnomAD v4.1: highest subpopulation is European (non-Finnish), AF 8.474834825469252e-07 = 0.00008474834825469252%, 1/1,179,964 alleles, homozygotes 0; total AF 6.196040234606868e-07, 1/1,613,934 alleles.
  • gnomAD v2.1 exome: highest subpopulation AF 0 in African/African American, 0/16,164 alleles, homozygotes 0; total AF 0, 0/250,488 alleles, homozygotes 0.
  • The governing ATM VCEP text specifies gnomAD but does not require a non-cancer or exome-only subset for PM2, so the all-comers gnomAD v2.1 and v4.1 entries are the applicable defaults.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Not met · 4 · evaluated, threshold not reached

BA1 VCEPNot met: the highest observed gnomAD subpopulation frequency is 8.474834825469252e-07, far below the >0.5% BA1 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies BA1 when the gnomAD group-maximum filtering allele frequency is >0.5%. The variant's highest observed gnomAD v4.1 subpopulation frequency is 8.474834825469252e-07 (1/1,179,964 alleles; European non-Finnish), and gnomAD v2.1 reports 0/16,164 alleles in its highest-frequency subpopulation, so neither reaches the VCEP threshold.

VCEP rule
Grpmax Filtering AF **>.5%** in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC BA1 rule: Grpmax Filtering AF >0.5% in gnomAD.
  • gnomAD v4.1: total AF 6.196040234606868e-07 (1/1,613,934 alleles; homozygotes 0); highest subpopulation AF 8.474834825469252e-07 in European (non-Finnish), 1/1,179,964 alleles, homozygotes 0.
  • gnomAD v2.1 exome: total AF 0 (0/250,488 alleles; homozygotes 0); highest subpopulation AF 0 in African/African American, 0/16,164 alleles, homozygotes 0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS1 VCEPNot met: the highest observed gnomAD subpopulation frequency is 8.474834825469252e-07, below the >0.05% BS1 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies BS1 when the gnomAD group-maximum filtering allele frequency is >0.05%. The variant's highest observed gnomAD v4.1 subpopulation frequency is 8.474834825469252e-07 (1/1,179,964 alleles; European non-Finnish), and gnomAD v2.1 reports 0/16,164 alleles in its highest-frequency subpopulation, so neither reaches the VCEP threshold.

VCEP rule
Grpmax Filtering AF **>.05%** in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC BS1 rule: Grpmax Filtering AF >0.05% in gnomAD.
  • gnomAD v4.1: total AF 6.196040234606868e-07 (1/1,613,934 alleles; homozygotes 0); highest subpopulation AF 8.474834825469252e-07 in European (non-Finnish), 1/1,179,964 alleles, homozygotes 0.
  • gnomAD v2.1 exome: total AF 0 (0/250,488 alleles; homozygotes 0); highest subpopulation AF 0 in African/African American, 0/16,164 alleles, homozygotes 0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS3 VCEPNot met: direct prime-editing classified the variant as Non-functional, providing impairment evidence rather than rescue of an ATM-specific feature or radiosensitivity. Details ▾Hide ▴
Reasoning

The exact variant row in Sun et al. 2025 Supplementary Table S1 is classified Non-functional with High confidence and DeepATM_predicted=No, which is direct prime-editing evidence of functional impairment rather than rescue of an ATM-specific feature or radiosensitivity. Therefore, the VCEP BS3 rule is not satisfied. The approved ATM assay-methodology table was searched for c.3077+1G>A and p.? and contains no variant-specific result that could support BS3.

VCEP rule
Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Evidence considered
  • Sun et al. 2025 Supplementary Table S1, row c.3077+1G>A: Classification=Non-functional; Confidence=High; DeepATM_predicted=No; this direct prime-editing result does not show rescue.
  • The VCEP approved-assay calibration file, sheets ATM kinase activity and ATM radiosensitivity, was searched using c.3077+1G>A and p.?; it lists methodology and calibration thresholds but no current-variant result.
Still missing
  • The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.3077+1G>A and p.?; no entry for this variant was found, and the table does not itself provide variant-specific assay results.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
BP4 VCEPNot met: SpliceAI max delta 0.992 exceeds the VCEP BP4 no-impact threshold of ≤0.1. Details ▾Hide ▴
Reasoning

The VCEP BP4 splicing path requires no predicted splice impact by SpliceAI at a maximum delta score of ≤0.1. SpliceAI reports a maximum delta score of 0.992 for NM_000051.4:c.3077+1G>A, so the required benign computational result is not present and BP4 is not met. The Table S1 row was reviewed but its functional classification is not used to double-count or establish BP4.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • SpliceAI Lookup reports DS_AG=0.003, DS_AL=0.191, DS_DG=0.644, DS_DL=0.992, with max delta score=0.992.
  • Sun et al. 2025, Supplementary Table S1, exact row c.3077+1G>A: Classification=Non-functional, Confidence=High, DeepATM_predicted=No; this functional result is not used for BP4.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Not assessed · 5 · no assessment recorded

PS1 VCEPNot assessed: the variant has a PVS1 baseline, but the PS1 splicing table has no matching reference-variant entry for c.3077+1G>A or p.?. Details ▾Hide ▴
Reasoning

The variant is a canonical +1 donor splice variant with NP_000042.3:p.? and is listed in the governing ATM PVS1 material as receiving PVS1 at very strong strength. However, the governing ATM PS1 splicing file contains no entry for c.3077+1G>A, p.?, or the c.3077+1 position identifying a known pathogenic or likely pathogenic reference variant with the same predicted splice event. Without that required comparator, PS1 cannot be assigned.

VCEP rule
* Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. ... * Prerequisite for all: The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant (e.g. both predicted to lead to exon A skipping, or both to enhanced use of cryptic site B), AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant.
Evidence considered
  • Variant normalization: NM_000051.4:c.3077+1G>A; protein consequence NP_000042.3:p.?; canonical splice donor (+1) at exon 20.
  • ATM_PVS1_1.6.pdf.txt, variant-specific list: c.3077+1G>A -> PVS1 (list A; N-terminal HEAT repeats; reading frame disrupted, NMD predicted) = very strong.
  • ATM_PS1_1.6.pdf.txt, PS1 splicing table: no row or variant-specific entry was found for c.3077+1G>A, p.?, or 3077+1.
  • The ATM PS1 table requires the predicted event of the variant under assessment to precisely match the predicted event of the known (likely) pathogenic variant, with similar or higher prediction strength; no qualifying reference variant was available in the governing file.
Still missing
  • ATM_PS1_1.6.pdf.txt was searched for c.3077+1G>A, p.?, and 3077+1; no entry for this variant or a qualifying same-event reference variant was found.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗vcep_atm_pvs1_1_6 ↗
PS4 VCEPNot assessed: the available study reported gene-level ATM OR 1.88 (95% CI 1.10–3.22, P=.02), not variant-specific case-control evidence for c.3077+1G>A. Details ▾Hide ▴
Reasoning

The ATM VCEP requires case-control evidence with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥2 or a lower 95% confidence interval ≥1.5. The available study is a case-case analysis of aggressive versus non-aggressive prostate cancer and reports a gene-level ATM association (OR=1.88, 95% CI=1.10–3.22, P=.02), but it does not report this exact variant, NM_000051.4:c.3077+1G>A, or variant-level case-control counts. Therefore the VCEP PS4 rule cannot be evaluated for this variant.

VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥2 **or** lower 95% CI ≥1.5).
Evidence considered
  • ATM gene-level case-case study: 1.6% of aggressive versus 0.8% of non-aggressive prostate cancer cases carried P/LP/D ATM alleles; OR=1.88, 95% CI=1.10–3.22, P=.02. The study did not mention NM_000051.4:c.3077+1G>A and did not provide variant-specific case-control data.
Still missing
  • Variant-level case-control counts or a variant-specific prevalence/enrichment estimate with p-value and confidence interval are unavailable.
Sources
PMID:32853339 ↗
PM3 VCEPNot assessed: no affected A-T proband, phase, or pathogenic variant-in-trans observation is available to assign the VCEP's PM3 points. Details ▾Hide ▴
Reasoning

PM3 is applicable to this ATM variant because the VCEP defines it for recessive ataxia-telangiectasia when the variant is detected in trans with a pathogenic variant and assigns strength from the accumulated proband points. The case evidence provides no affected A-T proband observation, phase determination, pathogenic variant in trans, homozygous observation, or phenotype classification from which to assign PM3 points. The governing ATM_PM3_BP2_1.6.pdf was searched for c.3077+1G>A and p.?; no entry for this variant was found. Therefore, PM3 cannot be assessed without substituting unprovided phase or proband evidence.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant
Evidence considered
  • The VCEP ATM PM3/BP2 points table was searched for c.3077+1G>A and p.?; neither notation produced a row for this variant.
  • The available case evidence identifies NM_000051.4:c.3077+1G>A / NP_000042.3:p.? but does not document an affected A-T proband, phase, or a pathogenic ATM variant in trans.
  • The VCEP PM3 table requires proband phenotype and allelic configuration to assign points; no point value can be assigned from the available evidence.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.3077+1G>A and p.?; no entry for this variant was found.
  • No affected A-T proband observation with phenotype classification and allele phase is available.
  • No confirmed pathogenic or likely pathogenic ATM variant in trans, homozygous observation, or other VCEP-eligible allelic configuration is documented.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗
PP1 VCEPNot assessed: no documented affected relatives or segregation results are available to meet the VCEP's 1-, 2-, or 3-relative thresholds. Details ▾Hide ▴
Reasoning

The ATM VCEP PP1 rule assigns supporting, moderate, or strong evidence according to segregation in 1, 2, or at least 3 affected relatives, respectively, under the AR condition. The available case evidence contains no documented affected relatives, parental testing, meioses, or segregation results for NM_000051.4:c.3077+1G>A, so the rule cannot be evaluated.

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
  • ClinGen HBOP ATM VCEP v1.6 PP1 rule: AR Condition: Segregation in 1 affected relative = Supporting; 2 affected relatives = Moderate; ≥3 affected relatives = Strong.
  • The case evidence provides no documented parental testing, affected-relative genotypes, meioses, or segregation count for this variant.
Still missing
  • Documented segregation testing and phenotypes for affected relatives, including the number of informative affected relatives.
Sources
cspec ↗
BP7 VCEPNot assessed: BP7(RNA) requires observed absence of an aberrant RNA defect, and no qualifying RNA result is available for this canonical donor +1 variant. Details ▾Hide ▴
Reasoning

The variant is a canonical donor +1 splice variant, so the non-RNA BP7 path for synonymous and deep intronic variants beyond +7 or -21 is outside scope. However, the VCEP also provides a BP7(RNA) path for intronic variants when an observed lack of aberrant RNA defect is available. No qualifying observed RNA result for this variant is available, so BP7 cannot be assessed.

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 normalization identifies NM_000051.4:c.3077+1G>A as a canonical splice donor (+1) variant, not a synonymous or deep intronic variant.
  • No observed RNA study demonstrating lack of an aberrant RNA defect was identified for this variant in the reviewed case evidence.
Still missing
  • An observed RNA study demonstrating lack of an aberrant RNA defect for NM_000051.4:c.3077+1G>A is unavailable.
Sources
cspec ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPNot applicable: the ATM VCEP explicitly marks PS2 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP specification explicitly marks PS2 as Not Applicable; therefore de novo evidence is not evaluated under this framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criteria entry for PS2: Applicability = Not Applicable.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP excludes PM1 because benign and pathogenic variants occur in the same domains and 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.

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 CSPEC PM1 entry: Do not use because benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.
Sources
cspec ↗
PM4 N/ANot applicable: PM4 is restricted to stop-loss variants, whereas c.3077+1G>A is a canonical splice-site substitution producing p.?. Details ▾Hide ▴
Reasoning

The variant is a canonical splice-site substitution producing p.?, not a stop-loss variant. The ATM VCEP PM4 rule is limited to stop-loss variants, so PM4 is not applicable.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • ATM VCEP CSPEC PM4 entry: the criterion is used for stop-loss variants only.
  • Case normalization: NM_000051.4:c.3077+1G>A has protein consequence NP_000042.3:p.? and canonical splice donor (+1) consequence.
Sources
cspec ↗
PM5 N/ANot applicable: this is a predicted splice variant without RNA data, which the ATM PM5 rule expressly excludes. Details ▾Hide ▴
Reasoning

The ATM VCEP PM5 rule applies to NMD-prone truncating variants with PVS1 at very strong strength, or to observed NMD-prone splice variants with PVS1(RNA) at very strong strength and high-quality RNA data. It expressly excludes predicted splice impact without RNA data. This variant has predicted canonical splice impact and no observed RNA result in the available evidence.

VCEP rule
* 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 CSPEC PM5 rule: splice variants require observed, not predicted, NMD-prone truncation, PVS1(RNA) at very strong strength, and high-quality RNA data; predicted splice impact without RNA data is excluded.
  • The case evidence identifies NM_000051.4:c.3077+1G>A as a canonical donor (+1) splice variant and provides no high-quality observed RNA result for this variant.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗
PM6 VCEPNot applicable: the ATM VCEP explicitly marks PM6 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP specification explicitly marks PM6 as Not Applicable; therefore presumed de novo evidence is not evaluated under this framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criteria entry for PM6: Applicability = Not Applicable.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP states that ATM lacks a defined low rate of benign missense variation. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly makes PP2 not applicable because ATM does not have a defined low rate of benign missense variation.

VCEP rule
Do not use: ATM does not have a defined low rate of missense benign variation.
Evidence considered
  • ATM CSPEC PP2 entry: Do not use because ATM does not have a defined low rate of missense benign variation.
Sources
cspec ↗
PP3 N/ANot applicable: the VCEP's PP3 splicing path excludes donor and acceptor 1,2 sites, and this variant is the canonical donor +1. Details ▾Hide ▴
Reasoning

The variant is a canonical donor +1 splice variant (NM_000051.4:c.3077+1G>A; NP_000042.3:p.?). The VCEP PP3 splicing rule expressly applies SpliceAI predicted impact to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites; therefore PP3 is not applicable to this canonical donor-site variant, regardless of the available SpliceAI max delta of 0.992. The exact governing Table S1 row was also found as c.3077+1G>A with Classification=Non-functional, Confidence=High, and DeepATM_predicted=No, but that functional result is not used to create PP3 evidence.

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 normalization identifies NM_000051.4:c.3077+1G>A as a canonical splice donor (+1) variant with NP_000042.3:p.?.
  • SpliceAI Lookup reports DS_AG=0.003, DS_AL=0.191, DS_DG=0.644, DS_DL=0.992, and max delta score=0.992.
  • Sun et al. 2025, Supplementary Table S1, exact row c.3077+1G>A: Classification=Non-functional, Confidence=High, DeepATM_predicted=No; this was reviewed as governing-file context but is not a PP3 predictor result.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for ATM-related breast cancer and incorporates autosomal-recessive phenotype evidence into the PM3/BP2 table. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP4 as not applicable for autosomal dominant ATM-related cancer predisposition because breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes; for autosomal recessive disease, PP4 is not used separately because phenotype evidence is built into the ATM 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's PP4 applicability instructions state that PP4 is not used for autosomal dominant ATM-related breast cancer and is not used separately for autosomal recessive disease.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP prohibits PP5, regardless of reputable-source classifications reporting this variant as pathogenic. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. ClinVar or other reputable-source classifications therefore cannot establish PP5 under this VCEP.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The VCEP PP5 entry is labeled 'Not Applicable for this VCEP' and instructs: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly makes BS2 not applicable because ATM has incomplete penetrance; therefore healthy-adult or homozygote observations cannot be evaluated under BS2, regardless of the absence of homozygotes in gnomAD.

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

The ATM VCEP specification explicitly marks BS4 as Not Applicable; therefore non-segregation evidence is not evaluated under this framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criteria entry for BS4: Applicability = Not Applicable.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP states that pathogenic missense variants are known for ATM. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly makes BP1 not applicable because missense pathogenic variants are known for ATM.

VCEP rule
Do not use: Missense pathogenic variants are known for ATM
Evidence considered
  • ATM CSPEC BP1 entry: Do not use because missense pathogenic variants are known for ATM.
Sources
cspec ↗
BP2 N/ANot applicable: canonical c.3077+1G>A has SpliceAI maximum delta 0.992, conflicting with the VCEP requirement that BP2 variants lack predicted clinically important splicing effects. Details ▾Hide ▴
Reasoning

BP2 is not applicable under the VCEP's ATM PM3/BP2 rule because the variant is a canonical donor (+1) splice variant with a bioinformatically predicted splice effect (SpliceAI maximum delta score 0.992). The VCEP specifically restricts its BP2 path to a variant under assessment that is not bioinformatically predicted, or experimentally proven, to have a clinically important effect on protein or mRNA splicing. The governing ATM_PM3_BP2_1.6.pdf was searched for c.3077+1G>A and p.?; no entry for this variant was found, so no pre-assigned BP2 code overrides the VCEP applicability restriction.

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. ... VUA should not be bioinformatically predicted (or experimentally proven) to have a clinically important effect on protein or mRNA splicing.
Evidence considered
  • The case evidence classifies NM_000051.4:c.3077+1G>A as a canonical splice donor (+1) variant and reports SpliceAI DS_DL 0.992 and DS max 0.992.
  • The VCEP ATM PM3/BP2 table was searched for c.3077+1G>A and p.?; neither notation produced a row for this variant.
  • The VCEP BP2 footnote excludes variants bioinformatically predicted to have a clinically important effect on protein or mRNA splicing.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.3077+1G>A and p.?; no entry for this variant was found.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗
BP3 VCEPNot applicable: the ATM VCEP explicitly marks BP3 Not Applicable, and this variant is a canonical splice-site substitution rather than an in-frame repeat-region deletion. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC explicitly marks BP3 as Not Applicable. The variant is also a canonical splice-site substitution rather than an in-frame deletion in a repetitive region, so BP3 does not apply under this VCEP framework.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC BP3 entry: Applicability = Not Applicable.
  • Case consequence assessment identifies NM_000051.4:c.3077+1G>A as a canonical donor (+1) splice variant with NP_000042.3:p.?.
Sources
cspec ↗
BP5 VCEPNot applicable: the VCEP prohibits BP5 because ATM's low penetrance permits pathogenic variants to co-occur without a noticeable phenotype difference. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP5 as not applicable and instructs that it should not be used because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference and ATM has low penetrance.

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 BP5 instructions state: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2).'
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP prohibits BP6, regardless of reputable-source classifications reporting this variant as benign. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Reputable-source benign classifications therefore cannot establish BP6 under this VCEP.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • The VCEP BP6 entry is labeled 'Not Applicable for this VCEP' and instructs: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.3077+1G>A
Protein (HGVS p.)
NP_000042.3:p.?
GRCh38
chr11:108271407 G>A
GRCh37
chr11:108142134 G>A
Location and type
Intron 20 · canonical splice
ClinVar
220036
COSMIC
COSV109415800

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 1 / 1,613,934 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 0 / 250,488 alleles AF 0 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,934 alleles · 0 hom
European (non-Finnish)1 / 1,179,964 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0 · 0 / 250,488 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19604e-07; MAF= 0.00006%, 1/1613934 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47483e-07; MAF= 0.00008%, 1/1179964 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250488 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16164 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -85 bp
0.191
SpliceAI acceptor gainat -322 bp
0.003
SpliceAI donor lossat -1 bp
0.992
SpliceAI donor gainat +3 bp
0.644
Pangolin splice lossmagnitude shown
-0.891
Pangolin splice gain
0.815

Other predictors

REVEL
Not available
BayesDel
0.337

How the predictions were used

BP4 VCEPNot met: SpliceAI max delta 0.992 exceeds the VCEP BP4 no-impact threshold of ≤0.1. Details ▾Hide ▴
Reasoning

The VCEP BP4 splicing path requires no predicted splice impact by SpliceAI at a maximum delta score of ≤0.1. SpliceAI reports a maximum delta score of 0.992 for NM_000051.4:c.3077+1G>A, so the required benign computational result is not present and BP4 is not met. The Table S1 row was reviewed but its functional classification is not used to double-count or establish BP4.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • SpliceAI Lookup reports DS_AG=0.003, DS_AL=0.191, DS_DG=0.644, DS_DL=0.992, with max delta score=0.992.
  • Sun et al. 2025, Supplementary Table S1, exact row c.3077+1G>A: Classification=Non-functional, Confidence=High, DeepATM_predicted=No; this functional result is not used for BP4.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 VCEPNot assessed: BP7(RNA) requires observed absence of an aberrant RNA defect, and no qualifying RNA result is available for this canonical donor +1 variant. Details ▾Hide ▴
Reasoning

The variant is a canonical donor +1 splice variant, so the non-RNA BP7 path for synonymous and deep intronic variants beyond +7 or -21 is outside scope. However, the VCEP also provides a BP7(RNA) path for intronic variants when an observed lack of aberrant RNA defect is available. No qualifying observed RNA result for this variant is available, so BP7 cannot be assessed.

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 normalization identifies NM_000051.4:c.3077+1G>A as a canonical splice donor (+1) variant, not a synonymous or deep intronic variant.
  • No observed RNA study demonstrating lack of an aberrant RNA defect was identified for this variant in the reviewed case evidence.
Still missing
  • An observed RNA study demonstrating lack of an aberrant RNA defect for NM_000051.4:c.3077+1G>A is unavailable.
Sources
cspec ↗
PP3 N/ANot applicable: the VCEP's PP3 splicing path excludes donor and acceptor 1,2 sites, and this variant is the canonical donor +1. Details ▾Hide ▴
Reasoning

The variant is a canonical donor +1 splice variant (NM_000051.4:c.3077+1G>A; NP_000042.3:p.?). The VCEP PP3 splicing rule expressly applies SpliceAI predicted impact to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites; therefore PP3 is not applicable to this canonical donor-site variant, regardless of the available SpliceAI max delta of 0.992. The exact governing Table S1 row was also found as c.3077+1G>A with Classification=Non-functional, Confidence=High, and DeepATM_predicted=No, but that functional result is not used to create PP3 evidence.

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 normalization identifies NM_000051.4:c.3077+1G>A as a canonical splice donor (+1) variant with NP_000042.3:p.?.
  • SpliceAI Lookup reports DS_AG=0.003, DS_AL=0.191, DS_DG=0.644, DS_DL=0.992, and max delta score=0.992.
  • Sun et al. 2025, Supplementary Table S1, exact row c.3077+1G>A: Classification=Non-functional, Confidence=High, DeepATM_predicted=No; this was reviewed as governing-file context but is not a PP3 predictor result.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.337185.

8 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Sun et al. 2025
    Sun et al. 2025 Supplementary Table S1 reports the exact ATM variant c.3077+1G>A as Non-functional with High confidence and DeepATM_predicted=No, so the classification is based on direct prime-editing assessment rather than a computational prediction.
    → PS3 · supporting Names this variant
    PMID 40580951 ↗
    Source detail
    108271407 G A c.3077+1G>A exon_20 11 Splice_AD 35 NA NA NA NA 6.84133039247344e-07 Likely pathogenic -3.24742909184742 Non-functional High No

    Location Supplementary Table S1, row c.3077+1G>A

    Context Genome-wide ATM SNV functional assessment using prime editing; this row is labeled as a direct measurement because DeepATM_predicted=No.

Other recorded publications

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.
    Darst BF et al. · 2021
    The study evaluated rare germline variants in 155 DNA-repair genes among 5,545 European-ancestry men with prostate cancer, including 2,770 aggressive and 2,775 non-aggressive cases. For ATM overall, 1.6% of aggressive cases and 0.8% of non-aggressive cases carried variants classified as pathogenic, likely pathogenic, or deleterious; the gene-level association was OR=1.88, 95% CI=1.10–3.22, P=.02. The exact ATM variant NM_000051.4:c.3077+1G>A was not mentioned, and variant-specific case-control observations were not provided.
    Does not name this variant
    PMID 32853339 ↗
    Quoted passage
    ATM was nominally associated with aggressive PCa, with 1.6% of aggressive and 0.8% of non-aggressive cases carrying P/LP/D ATM alleles (OR=1.88, 95% CI=1.10 to 3.22, P=.02).

    Results, 'Aggressive versus Non-Aggressive PCa' paragraph 2; Abstract, Results

  • Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
    No paper-specific finding is recorded.
    PMID 34242744 ↗
  • Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
    No paper-specific finding is recorded.
    PMID 24366376 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    No paper-specific finding is recorded.
    PMID 25394175 ↗
  • Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.
    No paper-specific finding is recorded.
    PMID 26389210 ↗
  • ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
    No paper-specific finding is recorded.
    PMID 34012068 ↗
  • Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey.
    Bora E et al. · 2022
    No paper-specific finding is recorded.
    PMID 35220195 ↗

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

gnomAD v4.1 1 / 1,613,934 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.992 Open source ↗
ClinVar 4 Likely pathogenic · 1 Pathogenic Open source ↗
COSMIC Captured COSMIC 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

This variant is present in gnomAD v4.1 (AF= 6.19604e-07; MAF= 0.00006%, 1/1613934 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47483e-07; MAF= 0.00008%, 1/1179964 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250488 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16164 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (4 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 220036)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.337185.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV109415800, n = 5 times).