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ATMc.1065+1G>CPathogenic
Print report
Variant interpretation report

ATM c.1065+1G>C, p.?

NM_000051.4:c.1065+1G>C NP_000042.3:p.? Canonical splice · intron 8 View identifiers
Classification
Pathogenic

Variant description:

The ATM NM_000051.4:c.1065+1G>C (NP_000042.3:p.?) splicing variant has previously been reported in somatic cancers (COSMIC; COSV53780484, n = 1 time). 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 testing classified c.1065+1G>C 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 at very strong: the ATM VCEP exact-row assignment for c.1065+1G>C states disrupted reading frame and predicted NMD in N-terminal HEAT repeats.

PS3Supporting
PS3 · supporting

Met at Supporting: direct prime-editing testing classified c.1065+1G>C as Non-functional with High confidence and DeepATM_predicted=No.

PM2Supporting
PM2 · supporting

Met at Supporting: the highest observed gnomAD subpopulation frequency is 0% because the variant is absent from both gnomAD v2.1 and v4.1, below the <=0.001% threshold.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: ATM VCEP Rule4 is satisfied by PVS1 very strong plus PS3 and PM2 supporting.

02The sources

Evidence at a glance

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

SpliceAI score
0.973 maximum delta

Recorded SpliceAI maximum delta score: 0.973. Refer to the recorded PP3/BP4 rationale for interpretation.

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

2 Likely pathogenic. ClinVar API review status: criteria provided, single submitter.

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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53780484, n = 1 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 · 5 not met · 5 not assessed · 15 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 ATM VCEP assigns PVS1 at very strong strength by exact variant row; PM4 is not met because the variant is not stop-loss, and BP3 is not applicable because the VCEP says not to use it.

PS2, PM6, and BS4 are explicitly not applicable under the ATM VCEP v1.6 CSPEC.

PP1 cannot be assessed because no affected-relative segregation or parental-testing data are documented, and the VCEP PP1 rule requires autosomal-recessive segregation in affected relatives.

Only PS4 is applicable under the ATM VCEP; the available case-control study supports a gene-level ATM association but does not provide variant-specific evidence for NM_000051.4:c.1065+1G>C.

PP4, PP5, BP5, and BP6 are explicitly not applicable under the ATM VCEP Version 1.6 rules.

Met · 3

PVS1 Very strongVCEPMet at very strong: the ATM VCEP exact-row assignment for c.1065+1G>C states disrupted reading frame and predicted NMD in N-terminal HEAT repeats. Details ▾Hide ▴
Reasoning

The governing ATM VCEP PVS1 table contains an exact pre-assigned entry for c.1065+1G>C: PVS1, list A, N-terminal HEAT repeats, reading frame disrupted, NMD predicted, very strong. The case evidence identifies this as the canonical donor +1 splice variant in exon 8 of the constitutive ATM transcript; exon skipping removes 164 coding nucleotides (164 % 3 = 2), shifts the reading frame, and is predicted to undergo NMD. The exact VCEP table entry controls the call and requires no downgrade.

VCEP rule
c.1065+1G>C -> PVS1 (list A; N-terminal HEAT repeats; reading frame disrupted, NMD predicted) = very strong
Evidence considered
  • ATM_PVS1_1.6.pdf, exact row: c.1065+1G>C -> PVS1 (list A; N-terminal HEAT repeats; reading frame disrupted, NMD predicted) = very strong.
  • Variant-level consequence facts: NM_000051.4:c.1065+1G>C is a canonical donor (+1) splice variant affecting exon 8; skipping exon 8 removes 164 coding nucleotides, with 164 % 3 = 2 and a shifted reading frame.
  • The ATM VCEP transcript guidance treats the relevant exons as constitutive without major alternate splice isoforms that could rescue presumed loss-of-function events.
Sources
vcep_atm_pvs1_1_6 ↗pvs1_variant_assessmentcspec ↗
PS3 SupportingVCEPMet at Supporting: direct prime-editing testing classified c.1065+1G>C 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.1065+1G>C, classified as Non-functional with Confidence=High and DeepATM_predicted=No. Under the governing VCEP curation rule for this table, DeepATM_predicted=No identifies a direct prime-editing measurement, and a Non-functional classification supports PS3_Supporting. This direction is consistent with the VCEP PS3 rule for a variant that fails to rescue an ATM-specific feature. The approved-assay methodology table was searched for c.1065+1G>C and p.?; it contains assay calibration and control information but no variant-specific entry, so it cannot independently add PS3 weight. The row's Combined_score is -6.91745656154298 and its Classification is Non-functional; no conflicting approved-assay result was identified.

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 ATM c.1065+1G>C: Classification=Non-functional, Confidence=High, DeepATM_predicted=No, Combined_score=-6.91745656154298, ClinVar_classification=Likely pathogenic.
  • The VCEP's table-specific PS3/BS3 rule treats DeepATM_predicted=No with High, Medium-high, or Medium confidence as direct prime-editing measurement and assigns PS3_Supporting for Classification=Non-functional.
  • ClinGen HBOP ATM Supplementary Tables 1 and 2 were searched for c.1065+1G>C and p.?; the file contains approved assay methodology and strength calibration, but no variant-specific result for this variant.
  • The VCEP PS3 Supporting rule applied was: 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
Still missing
  • The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.1065+1G>C and p.?; no variant-specific entry was found, so its calibrated assays do not independently contribute evidence for this variant.
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 observed gnomAD subpopulation frequency is 0% because the variant is absent from both gnomAD v2.1 and v4.1, below the <=0.001% threshold. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.6 PM2 rule applies PM2 at Supporting strength when frequency is at most 0.001% in the gnomAD subpopulation with the highest frequency, with a single-observation exception. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so the highest observed subpopulation frequency is 0%, meeting PM2_Supporting. The VCEP does not specify a non-cancer or exome-only subset for PM2, so the available all-comers gnomAD results are the applicable default.

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 instructions specify PM2_Supporting rather than moderate PM2.
  • gnomAD v2.1: variant absent; no observed alleles or subpopulation frequency reported, corresponding to an observed frequency of 0%.
  • gnomAD v4.1: variant absent; no observed alleles or subpopulation frequency reported, corresponding to an observed frequency of 0%.
  • The VCEP rule names gnomAD without requiring a non-cancer or exome-only subset; therefore the all-comers gnomAD results are used.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not met · 5 · evaluated, threshold not reached

PM4 VCEPNot met: PM4 is restricted to stop-loss variants, whereas c.1065+1G>C is a canonical splice-donor variant producing a predicted frameshift and p.?. Details ▾Hide ▴
Reasoning

The ATM VCEP limits PM4 to stop-loss variants. This variant is a canonical splice-donor substitution with predicted exon skipping and a frameshift, producing p.?; it is not a stop-loss variant and does not meet the VCEP PM4 applicability rule.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • ATM VCEP PM4 rule: the criterion is for stop-loss variants only.
  • Variant consequence facts: canonical splice donor (+1) substitution, predicted exon 8 skipping with a shifted reading frame, and protein annotation NP_000042.3:p.?.
Sources
cspec ↗pvs1_variant_assessment
BA1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, so its group-maximum allele frequency does not exceed the VCEP's >0.5% BA1 threshold. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.6 BA1 threshold is a group maximum filtering allele frequency greater than 0.5% in gnomAD. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no population frequency exceeds the BA1 threshold. The VCEP does not specify a non-cancer or exome-only subset for BA1, so the available all-comers gnomAD results are the applicable default.

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 v2.1: variant absent; source_data is empty, so observed allele count and allele frequency are 0/not observed.
  • gnomAD v4.1: variant absent; source_data is empty, so observed allele count and allele frequency are 0/not observed.
  • The VCEP rule names gnomAD without requiring a non-cancer or exome-only subset; therefore the all-comers gnomAD results are used.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, so its group-maximum allele frequency does not exceed the VCEP's >0.05% BS1 threshold. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.6 BS1 threshold is a group maximum filtering allele frequency greater than 0.05% in gnomAD. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so no population frequency exceeds the BS1 threshold. The VCEP does not specify a non-cancer or exome-only subset for BS1, so the available all-comers gnomAD results are the applicable default.

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 v2.1: variant absent; source_data is empty, so observed allele count and allele frequency are 0/not observed.
  • gnomAD v4.1: variant absent; source_data is empty, so observed allele count and allele frequency are 0/not observed.
  • The VCEP rule names gnomAD without requiring a non-cancer or exome-only subset; therefore the all-comers gnomAD results are used.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 VCEPNot met: direct prime-editing testing classified c.1065+1G>C as Non-functional, not Functional, with High confidence. Details ▾Hide ▴
Reasoning

The exact variant row in Sun et al. 2025 Supplementary Table S1 is a direct prime-editing measurement because DeepATM_predicted=No with Confidence=High, and it is classified Non-functional rather than Functional. The governing table-specific rule therefore assigns PS3_Supporting, not BS3_Supporting. The VCEP BS3 Supporting rule requires rescue of either an ATM-specific feature or radiosensitivity; the available direct result shows non-function rather than rescue. The approved-assay methodology table was searched for c.1065+1G>C and p.? and has no variant-specific entry, so it provides no contrary benign functional result.

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 ATM c.1065+1G>C: Classification=Non-functional, Confidence=High, DeepATM_predicted=No, Combined_score=-6.91745656154298.
  • The VCEP's table-specific PS3/BS3 rule assigns BS3_Supporting only when DeepATM_predicted=No with High, Medium-high, or Medium confidence and Classification=Functional; this row does not meet that condition.
  • The VCEP BS3 Supporting rule applied was: Use when a variant rescues EITHER an ATM specifc feature or rescues radiosensitivity.
  • ClinGen HBOP ATM Supplementary Tables 1 and 2 were searched for c.1065+1G>C and p.?; the file contains assay methodology and calibration but no variant-specific result.
Still missing
  • The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.1065+1G>C and p.?; no variant-specific entry was found, so no approved-assay rescue result is available from that file.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
BP4 VCEPNot met: SpliceAI maximum delta score is 0.973, exceeding the VCEP BP4 no-impact threshold of <=0.1. Details ▾Hide ▴
Reasoning

The ATM VCEP BP4 splicing rule requires no predicted splice impact with SpliceAI <=0.1. SpliceAI predicts substantial splice impact for this canonical donor +1 variant, with a maximum delta score of 0.973, which exceeds the benign threshold; BP4 is therefore not met.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • ATM VCEP v1.6 BP4 splicing rule: no predicted impact via splicing requires SpliceAI <=0.1.
  • SpliceAI result for NM_000051.4:c.1065+1G>C: DS_AG 0.02, DS_AL 0.0, DS_DG 0.267, DS_DL 0.973; maximum delta score 0.973, indicating predicted splice impact.
Sources
cspec ↗spliceai ↗

Not assessed · 5 · no assessment recorded

PS1 VCEPNot assessed: the ATM PS1 splicing table contains no c.1065+1G>C or p.? comparator entry, so no pre-assigned PS1 code can be applied. Details ▾Hide ▴
Reasoning

The variant is a canonical donor +1 splice substitution (c.1065+1G>C; p.?), and the ATM PS1 splicing table was searched for c.1065+1G>C and p.? without finding an entry for this variant or a known pathogenic comparator. The VCEP requires a reference variant with the same predicted splicing event and comparable or stronger prediction before assigning PS1; the available SpliceAI score of 0.973 does not by itself establish that comparator relationship.

VCEP rule
Splicing: 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
  • Case normalization identifies NM_000051.4:c.1065+1G>C with protein consequence NP_000042.3:p.? and canonical splice donor (+1) consequence.
  • ATM_PS1_1.6.pdf.txt was searched for c.1065+1G>C and p.?; no matching variant or comparator row was found.
  • SpliceAI max delta score is 0.973 (DS_DL 0.973), but no VCEP-qualified reference variant with the same predicted event was identified.
Still missing
  • No entry for c.1065+1G>C or p.? was found in ATM_PS1_1.6.pdf.txt; a qualifying known pathogenic or likely pathogenic comparator with the same predicted splice event is not available.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗spliceai ↗
PS4 VCEPNot assessed: gene-level ATM pathogenic variants showed OR=2.1 and p=0.031, but the study did not identify NM_000051.4:c.1065+1G>C specifically. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PS4 Strong for case-control studies when p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5). The available case-control study reported gene-level pathogenic ATM variants in 7,051 breast-cancer cases and 11,241 controls, with p=0.031 and OR=2.1 (95% CI 1.0–4.1); the threshold comparison is p=0.031 ≤ 0.05? yes, and OR=2.1 ≥ 2? yes. However, the study did not identify or report NM_000051.4:c.1065+1G>C specifically (variant_mentioned=false), so variant-level PS4 cannot be evaluated from this evidence.

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
  • ClinGen HBOP ATM VCEP Version 1.6 PS4 Strong rule: case-control studies require p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).
  • Momozawa et al. 2018, Table 2/Table 3, ATM row: 27 pathogenic ATM variants occurred in 22 of 7,051 breast-cancer cases (0.31%) and 17 of 11,241 controls (0.15%), p=0.031, OR=2.1, 95% CI 1.0–4.1; the paper does not explicitly mention c.1065+1G>C.
Still missing
  • Variant-specific case-control counts or a VCEP-acceptable set of unrelated affected individuals and controls for NM_000051.4:c.1065+1G>C are unavailable.
Sources
cspec ↗PMID:30287823 ↗
PM3 VCEPNot assessed: no affected-proband, phase, or pathogenic-in-trans evidence was available, and ATM_PM3_BP2_1.6.pdf contains no entry for c.1065+1G>C or p.?. Details ▾Hide ▴
Reasoning

The ATM VCEP PM3 rule requires the variant to be detected in trans with a pathogenic variant and assigns points according to the Ataxia Telangiectasia PM3/BP2 table. The case evidence contains no affected A-T proband observation, phase result, second pathogenic ATM variant, homozygous observation, or phenotype/laboratory data sufficient to score a proband. The governing file ATM_PM3_BP2_1.6.pdf was searched for c.1065+1G>C and p.?; no entry for this variant was found. Therefore no PM3 points or strength can be assigned.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant
Evidence considered
  • The ATM VCEP CSPEC entry states that PM3 uses the ATM PM3/BP2 table and assigns PM3 strength from the summed PM3-related points.
  • ATM_PM3_BP2_1.6.pdf states: 'For recessive disorders, detected in trans with a pathogenic variant' and provides per-unrelated-A-T-proband points based on phenotype and zygosity/phase.
  • The consolidated allelic evidence contains no affected-proband, phase, trans/cis, homozygous, or pathogenic-partner observation for NM_000051.4:c.1065+1G>C.
  • ATM_PM3_BP2_1.6.pdf was searched for c.1065+1G>C and p.?; no variant-specific table entry was found.
Still missing
  • No affected Ataxia-Telangiectasia proband observation with phenotype classification and laboratory results sufficient for the VCEP PM3 table.
  • No confirmed-in-trans, phase-unknown, homozygous, or second-variant-unidentified/VUS configuration was documented.
  • No entry for c.1065+1G>C or p.? was found after searching ATM_PM3_BP2_1.6.pdf.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗
PP1 Not assessed: no affected-relative segregation data are documented to evaluate the VCEP's autosomal-recessive PP1 thresholds. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 defines PP1 for autosomal-recessive disease as segregation in affected relatives, with Supporting for one, Moderate for two, and Strong for at least three affected relatives. The available case evidence documents no affected-relative segregation results, parental testing, or meioses that can be evaluated under this rule.

Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC PP1 rules: AR Condition—segregation in 1 affected relative = Supporting; 2 affected relatives = Moderate; at least 3 affected relatives = Strong.
  • No affected-relative segregation, parental testing, phase, or informative-meiosis results are documented in the case evidence provided for this assessment.
Still missing
  • Affected-relative genotypes and phenotypes
  • Parental testing and phase information
  • Number of informative meioses
Sources
cspec ↗
BP2 VCEPNot assessed: no cis/trans pathogenic-partner observation or unaffected-adult BP2 data was available, and ATM_PM3_BP2_1.6.pdf contains no entry for c.1065+1G>C or p.?. Details ▾Hide ▴
Reasoning

The ATM VCEP BP2 rule requires observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observation in cis with a pathogenic variant, with strength assigned from the BP2 points in the Ataxia Telangiectasia PM3/BP2 table. The case evidence contains no documented cis or trans relationship, unaffected adult proband, pathogenic partner variant, or laboratory/database setting needed to score BP2. The governing file ATM_PM3_BP2_1.6.pdf was searched for c.1065+1G>C and p.?; no entry for this variant was found. Therefore BP2 cannot be assessed.

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
  • The ATM VCEP CSPEC entry states that BP2 uses the ATM PM3/BP2 table and assigns BP2 strength from the summed BP2-related points.
  • ATM_PM3_BP2_1.6.pdf states: '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 specifies that an unaffected individual assessed for an in-trans or homozygous observation should be an adult over 18 years with no evidence of A-T.
  • The consolidated allelic evidence contains no cis/trans observation, pathogenic partner, unaffected adult, or BP2 scoring data for NM_000051.4:c.1065+1G>C.
  • ATM_PM3_BP2_1.6.pdf was searched for c.1065+1G>C and p.?; no variant-specific table entry was found.
Still missing
  • No documented observation of the variant in cis or in trans with a pathogenic or likely pathogenic ATM variant.
  • No unaffected adult observation with age, A-T status, phase/zygosity, and laboratory or database setting sufficient for BP2 scoring.
  • No entry for c.1065+1G>C or p.? was found after searching ATM_PM3_BP2_1.6.pdf.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPNot applicable: the ATM VCEP v1.6 explicitly marks PS2 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC entry explicitly marks PS2 as Not Applicable.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PS2: Applicability = Not Applicable.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP explicitly marks PM1 Not Applicable, and no authoritative ATM domain-table entry is present. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC marks PM1 as Not Applicable. The authoritative vcep_materials.json domain_tables object is empty, and the variant is a canonical splice-site variant rather than a missense change for which a critical functional domain assessment would apply.

VCEP rule
Not Applicable
Evidence considered
  • The ATM CSPEC criterion entry for PM1 states applicability: Not Applicable.
  • vcep_materials.json contains domain_tables: {} for ATM.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 requires observed splice impact with high-quality RNA and PVS1(RNA) Very Strong, whereas this variant has predicted splice impact without RNA data. Details ▾Hide ▴
Reasoning

The ATM VCEP PM5 rule for splice variants applies only to observed, not predicted, NMD-prone truncating variants with PVS1(RNA) at Very Strong strength and high-quality RNA data. This variant has a predicted canonical splice consequence with no RNA evidence, so the VCEP's explicit exclusion applies.

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
  • The ATM CSPEC PM5 rule states that splice variants require observed, not predicted, NMD-prone truncation, PVS1(RNA) at Very Strong strength, and high-quality RNA data; it excludes predicted splice impact without RNA data.
  • Case evidence identifies a canonical donor (+1) splice variant and does not provide RNA data or PVS1(RNA) evidence.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP v1.6 explicitly marks PM6 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC entry explicitly marks PM6 as Not Applicable.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PM6: Applicability = Not Applicable.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP explicitly marks PP2 Not Applicable for this interpretation. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC explicitly marks PP2 as Not Applicable; therefore no gene-level missense mechanism evidence is evaluated under PP2 for this case.

VCEP rule
Not Applicable
Evidence considered
  • The ATM CSPEC criterion entry for PP2 states applicability: Not Applicable.
Sources
cspec ↗
PP3 N/ANot applicable: c.1065+1G>C is a canonical donor +1 variant, outside the VCEP PP3 splicing scope for variants beyond donor/acceptor 1,2 sites. Details ▾Hide ▴
Reasoning

The variant is a canonical donor +1 splice variant (c.1065+1G>C), whereas the ATM VCEP PP3 splicing rule applies to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites. The canonical +1 position is therefore outside PP3's defined scope, even though SpliceAI reports a maximum delta score of 0.973.

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
  • ATM VCEP v1.6 PP3 rule: the splicing path is limited to predicted impact via SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
  • SpliceAI result for NM_000051.4:c.1065+1G>C: DS_AG 0.02, DS_AL 0.0, DS_DG 0.267, DS_DL 0.973; maximum delta score 0.973.
  • Variant consequence is canonical_splice at the donor (+1) site; the PP3 rule's outside-donor/acceptor-1,2 limitation makes this criterion not applicable.
Sources
cspec ↗spliceai ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for hereditary breast cancer and does not allow it separately for autosomal-recessive ataxia telangiectasia. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP4 not applicable: it excludes PP4 for autosomal-dominant breast cancer because of genetic heterogeneity and excludes it as a separate line for autosomal-recessive ataxia telangiectasia because the phenotype evidence is incorporated 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's PP4 applicability instructions state that PP4 is not used for autosomal-dominant breast cancer and is not used as a separate line of evidence for autosomal-recessive ataxia telangiectasia.
Sources
cspec ↗
PP5 VCEPNot applicable: the VCEP prohibits PP5, regardless of the available ClinVar likely-pathogenic submission. 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; ClinVar's likely-pathogenic submission therefore cannot establish PP5.

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

The ClinGen HBOP ATM VCEP v1.6 explicitly makes BS2 not applicable because ATM has incomplete penetrance; therefore no healthy-individual or homozygote observation can be used to apply BS2 under this governing framework.

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

The ATM VCEP v1.6 CSPEC entry explicitly marks BS4 as Not Applicable.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for BS4: Applicability = Not Applicable.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP explicitly marks BP1 Not Applicable for this interpretation. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC explicitly marks BP1 as Not Applicable; no benign evidence for a non-critical missense region is evaluated under BP1.

VCEP rule
Not Applicable
Evidence considered
  • The ATM CSPEC criterion entry for BP1 states applicability: Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP says not to use BP3, and this variant is a splice-donor substitution rather than an in-frame repeat-region indel. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly marks BP3 not applicable and instructs assessors not to use it. The variant is also not an in-frame insertion or deletion in a repetitive region; it is a canonical splice-donor substitution with predicted frameshift and NMD.

VCEP rule
Do not use.
Evidence considered
  • ATM VCEP BP3 entry: applicability is not applicable and the instruction is Do not use.
  • Variant consequence facts: canonical splice-donor substitution at c.1065+1G>C with predicted exon skipping, frameshift, and NMD; no in-frame insertion or deletion is present.
Sources
cspec ↗pvs1_variant_assessment
BP5 VCEPNot applicable: the VCEP prohibits BP5 because multiple pathogenic variants can coexist without a noticeable phenotype difference in low-penetrance ATM disease. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP5 not applicable and instructs reviewers not to use it because multiple pathogenic variants may occur 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's BP5 instructions state not to use BP5 because cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype and ATM has low penetrance.
Sources
cspec ↗
BP6 VCEPNot applicable: the VCEP prohibits BP6, so no reputable-source benign assertion can establish this criterion. 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's BP6 instructions state that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: c.1065+1G>C is a canonical donor +1 variant, not a synonymous or deep intronic variant beyond the VCEP BP7 boundaries. Details ▾Hide ▴
Reasoning

The ATM VCEP BP7 prediction path applies to synonymous and deep intronic variants farther than +7 at donor sites or farther than -21 at acceptor sites. c.1065+1G>C is a canonical donor +1 variant, not a synonymous or deep intronic variant, so BP7 is not applicable. No RNA-specific BP7(RNA) result was available.

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
  • ATM VCEP v1.6 BP7 rule limits BP7 to synonymous and deep intronic variants farther than +7 at donor sites and farther than -21 at acceptor sites.
  • Variant consequence is canonical_splice at the donor (+1) site; this is within the canonical donor/acceptor region and outside BP7's defined deep-intronic scope.
  • No observed RNA result demonstrating lack of an aberrant RNA defect was identified for this variant, so BP7(RNA) is not applicable either.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.1065+1G>C
Protein (HGVS p.)
NP_000042.3:p.?
GRCh38
chr11:108247128 G>C
GRCh37
chr11:108117855 G>C
Location and type
Intron 8 · canonical splice
ClinVar
551531
COSMIC
COSV53780484

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

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -1 bp
0.000
SpliceAI acceptor gainat -164 bp
0.020
SpliceAI donor lossat -1 bp
0.973
SpliceAI donor gainat +4 bp
0.267
Pangolin splice lossmagnitude shown
-0.870
Pangolin splice gain
0.731

Other predictors

REVEL
Not available
BayesDel
0.388

How the predictions were used

BP4 VCEPNot met: SpliceAI maximum delta score is 0.973, exceeding the VCEP BP4 no-impact threshold of <=0.1. Details ▾Hide ▴
Reasoning

The ATM VCEP BP4 splicing rule requires no predicted splice impact with SpliceAI <=0.1. SpliceAI predicts substantial splice impact for this canonical donor +1 variant, with a maximum delta score of 0.973, which exceeds the benign threshold; BP4 is therefore not met.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • ATM VCEP v1.6 BP4 splicing rule: no predicted impact via splicing requires SpliceAI <=0.1.
  • SpliceAI result for NM_000051.4:c.1065+1G>C: DS_AG 0.02, DS_AL 0.0, DS_DG 0.267, DS_DL 0.973; maximum delta score 0.973, indicating predicted splice impact.
Sources
cspec ↗spliceai ↗
PP3 N/ANot applicable: c.1065+1G>C is a canonical donor +1 variant, outside the VCEP PP3 splicing scope for variants beyond donor/acceptor 1,2 sites. Details ▾Hide ▴
Reasoning

The variant is a canonical donor +1 splice variant (c.1065+1G>C), whereas the ATM VCEP PP3 splicing rule applies to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites. The canonical +1 position is therefore outside PP3's defined scope, even though SpliceAI reports a maximum delta score of 0.973.

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
  • ATM VCEP v1.6 PP3 rule: the splicing path is limited to predicted impact via SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
  • SpliceAI result for NM_000051.4:c.1065+1G>C: DS_AG 0.02, DS_AL 0.0, DS_DG 0.267, DS_DL 0.973; maximum delta score 0.973.
  • Variant consequence is canonical_splice at the donor (+1) site; the PP3 rule's outside-donor/acceptor-1,2 limitation makes this criterion not applicable.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: c.1065+1G>C is a canonical donor +1 variant, not a synonymous or deep intronic variant beyond the VCEP BP7 boundaries. Details ▾Hide ▴
Reasoning

The ATM VCEP BP7 prediction path applies to synonymous and deep intronic variants farther than +7 at donor sites or farther than -21 at acceptor sites. c.1065+1G>C is a canonical donor +1 variant, not a synonymous or deep intronic variant, so BP7 is not applicable. No RNA-specific BP7(RNA) result was available.

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
  • ATM VCEP v1.6 BP7 rule limits BP7 to synonymous and deep intronic variants farther than +7 at donor sites and farther than -21 at acceptor sites.
  • Variant consequence is canonical_splice at the donor (+1) site; this is within the canonical donor/acceptor region and outside BP7's defined deep-intronic scope.
  • No observed RNA result demonstrating lack of an aberrant RNA defect was identified for this variant, so BP7(RNA) is not applicable either.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.97). BayesDel score = 0.388085.

6 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 contains the exact ATM variant c.1065+1G>C. The row is a splice variant in exon 8 with Combined_score -6.91745656154298, Classification Non-functional, Confidence High, and DeepATM_predicted No, indicating a direct prime-editing result rather than a computational prediction.
    → PS3 · supporting Names this variant
    PMID 40580951 ↗
    Source detail
    108247128 G C c.1065+1G>C exon_8 11 Splice_AD 34 NA NA NA NA 0 Likely pathogenic -6.91745656154298 Non-functional High No

    Location Supplementary Table S1, exact row c.1065+1G>C

    Context Genome-scale ATM SNV functional assessment using prime editing with deep-learning support; this exact row is marked DeepATM_predicted=No, so the Classification is treated under the VCEP table rule as a direct prime-editing measurement.

Other recorded publications

  • Hereditary Ataxia Overview.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301317 ↗
  • Ataxia-Telangiectasia.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301790 ↗
  • EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
    van de Warrenburg BP et al. · 2014
    No paper-specific finding is recorded.
    PMID 24418350 ↗
  • 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 ↗
  • Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.
    Momozawa Y et al. · 2018
    The paper does not explicitly mention ATM c.1065+1G>C or a corresponding protein change. At the gene level, sequencing of 7,051 female breast cancer cases and 11,241 female controls identified 27 ATM variants classified as pathogenic. These variants were present in 22 breast cancer cases (0.31%) and 17 controls (0.15%), showing a nominal association with breast cancer (P=0.031; OR=2.1, 95% CI 1.0–4.1).
    Does not name this variant
    PMID 30287823 ↗
    Quoted passage
    ATM 2722 (0.31)17 (0.15)0.0312.1(1.0–4.1)

    Table 2; Table 3

  • EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
    Gasser T et al. · 2010
    No paper-specific finding is recorded.
    PMID 20050888 ↗

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 0.973 Open source ↗
ClinVar 2 Likely 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely pathogenic (2 clinical laboratories). (ClinVarID = 551531)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.97). BayesDel score = 0.388085.

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV53780484, n = 1 times).