ATMc.6733G>ANot classified

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Variant interpretation report

ATM c.6733G>A, p.(Glu2245Lys)

NM_000051.4:c.6733G>A NP_000042.3:p.(Glu2245Lys) 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

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: ClinGen ATM VCEP v1.5.0
Other laboratories (ClinVar): 2 Uncertain significance
Pipeline record: 25 May 2026

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): Population frequency is below the ATM PM2_Supporting threshold. This variant is present in gnomAD v4.1 at 1/1,613,632 alleles (AF 6.1972e-07; 0.00006%), with highest observed subpopulation frequency 1/1,179,898 in European non-Finnish individuals (AF 8.4753e-07; 0.00008%), which is below the <=0.001% threshold; it is also absent from gnomAD v2.1 and gnomAD-Canada.
BP4 (supporting): Available computational evidence supports a benign interpretation. REVEL is 0.076, which is below the ATM BP4 missense threshold of <=0.249, and SpliceAI shows a max delta score of 0.02, which is below the ATM BP4 splicing threshold of <=0.1. BayesDel is also negative at -0.479783, which is consistent with a benign effect.

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 v1.5.0. 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

Population frequency is below the ATM PM2_Supporting threshold. This variant is present in gnomAD v4.1 at 1/1,613,632 alleles (AF 6.1972e-07; 0.00006%), with highest observed subpopulation frequency 1/1,179,898 in European non-Finnish individuals (AF 8.4753e-07; 0.00008%), which is below the <=0.001% threshold; it is also absent from gnomAD v2.1 and gnomAD-Canada.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Available computational evidence supports a benign interpretation. REVEL is 0.076, which is below the ATM BP4 missense threshold of <=0.249, and SpliceAI shows a max delta score of 0.02, which is below the ATM BP4 splicing threshold of <=0.1. BayesDel is also negative at -0.479783, which is consistent with a benign effect.

Recorded classification: Not classified

Richards et.al., 2015 - Combining rules v1.5.0 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.

gnomAD v4.1

gnomAD v2.1

Population frequency

1 / 1,613,632 alleles

gnomAD v4.1: 1 / 1,613,632 alleles. Recorded AF 6.1972e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

2 reported laboratory submissions

2 Uncertain significance.

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

2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV99589774, n = 2 times).

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 v1.5.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 6 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

The ATM NM_000051.4:c.6733G>A (p.(Glu2245Lys), p.(E2245K)) variant has been observed in somatic cancers in COSMIC (COSV99589774, n=2) and has been reported in ClinVar as a variant of uncertain significance by 2 clinical laboratories.

This variant is extremely rare in population databases, with gnomAD v4.1 showing 1/1613632 alleles overall (AF 6.1972e-07; 0.00006%) and a highest observed subpopulation frequency of 1/1179898 in European non-Finnish individuals (AF 8.4753e-07; 0.00008%), which is below the ATM PM2_Supporting threshold of <=0.001%; it is also absent from gnomAD v2.1 and gnomAD-Canada.

In a supplementary ATM functional resource, p.(Glu2245Lys) was classified as Functional with high confidence, but the currently available summary does not provide the criterion-aligned rescue assay detail required to apply ATM BS3.

Computational evidence supports a benign interpretation, with REVEL 0.076 below the ATM BP4 threshold of <=0.249, SpliceAI max delta 0.02 below the BP4 threshold of <=0.1 and below the PP3 threshold of >=0.2, and BayesDel -0.479783 in a benign direction.

Met · 2

PM2 SupportingPopulation frequency is below the ATM PM2_Supporting threshold. This variant is present in gnomAD v4.1 at 1/1,613,632 alleles (AF 6.1972e-07; 0.00006%), with highest observed subpopulation frequency 1/1,179,898 in European non-Finnish individuals (AF 8.4753e-07; 0.00008%), which is below the <=0.001% threshold; it is also absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴

Rule

ATM PM2_Supporting: frequency ≤0.001% in gnomAD v4

Evidence considered

gnomAD v4.1 total AF 6.1972e-07
gnomAD v4.1 highest subpopulation AF 8.4753e-07
Absent from gnomAD v2.1
Absent from gnomAD-Canada v1.0

Sources

cspec ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

BP4 SupportingAvailable computational evidence supports a benign interpretation. REVEL is 0.076, which is below the ATM BP4 missense threshold of <=0.249, and SpliceAI shows a max delta score of 0.02, which is below the ATM BP4 splicing threshold of <=0.1. BayesDel is also negative at -0.479783, which is consistent with a benign effect. Details ▾Hide ▴

Rule

ATM BP4: REVEL ≤0.249 and/or SpliceAI ≤0.1 as applicable

Evidence considered

REVEL 0.076
SpliceAI max delta 0.02
BayesDel -0.479783

Sources

cspec ↗revelspliceai ↗bayesdel

Not met · 3 · evaluated, threshold not reached

PP3 Available computational evidence does not support a damaging effect. REVEL is 0.076, which is below the ATM PP3 missense threshold of >0.7333, and SpliceAI shows a max delta score of 0.02, which is below the ATM PP3 splicing threshold of >=0.2. BayesDel is also negative at -0.479783. Details ▾Hide ▴

Rule

ATM PP3: REVEL >0.7333 and/or SpliceAI ≥0.2 as applicable

Evidence considered

REVEL 0.076
SpliceAI max delta 0.02
BayesDel -0.479783

Sources

cspec ↗revelspliceai ↗bayesdel

BA1 Population frequency does not meet the ATM BA1 threshold. The highest observed gnomAD v4.1 population frequency is 8.4753e-07 (0.00008%), which is far below the BA1 cutoff of >0.5%. Details ▾Hide ▴

Rule

ATM BA1: grpmax filtering AF >0.5% in gnomAD v4

Evidence considered

Highest observed gnomAD v4.1 population AF 8.4753e-07

Sources

cspec ↗gnomad_v4 ↗

BS1 Population frequency does not meet the ATM BS1 threshold. The highest observed gnomAD v4.1 population frequency is 8.4753e-07 (0.00008%), which is below the BS1 cutoff of >0.05%. Details ▾Hide ▴

Rule

ATM BS1: grpmax filtering AF >0.05% in gnomAD v4

Evidence considered

Highest observed gnomAD v4.1 population AF 8.4753e-07

Sources

cspec ↗gnomad_v4 ↗

Not assessed · 6 · no assessment recorded

PS3 No criterion-aligned functional study was identified showing that this variant fails to rescue an ATM-specific feature or fails to rescue both an ATM-specific feature and radiosensitivity, so PS3 is not currently supported. Details ▾Hide ▴

Rule

ATM-specific rescue assay requirements for PS3

Evidence considered

ATM-specific PS3 requires failure to rescue ATM-specific function
with moderate strength requiring failure to rescue both ATM-specific function and radiosensitivity.
The available ATM supplementary assay tables do not provide a criterion-ready PS3 assignment for this variant.

Still missing

Direct ATM rescue assay data for p.(Glu2245Lys)
Published assay details that match the ATM PS3 framework

Sources

cspec ↗vcep_atm_pvs1_1_5vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951

PS4 This variant has been reported in ClinVar and observed in somatic cancers, but no case-control study or exact affected-versus-control enrichment data were identified to meet the ATM PS4 requirement. Details ▾Hide ▴

Rule

Case-control studies with p≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5

Evidence considered

ClinVar reports uncertain significance submissions.
No ATM-specific case-control evidence was retrieved.

Still missing

Case-control data with p-value and effect size
Exact affected and control counts for this variant

Sources

cspec ↗clinvar ↗oncokb ↗PMID:28492532 ↗

PM3 No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an affected individual was identified, so PM3 cannot currently be applied. Details ▾Hide ▴

Rule

ATM PM3 point-based recessive evidence framework

Evidence considered

ATM PM3 requires point-based trans observations in affected individuals.

Still missing

Phase-confirmed trans observations
Phenotype-classified A-T probands carrying this variant with a pathogenic ATM allele

Sources

cspec ↗vcep_atm_pm3_bp2_1_5clinvar ↗

PP1 No segregation data were identified for this variant, so PP1 cannot currently be applied. Details ▾Hide ▴

Rule

AR condition: segregation in affected relatives

Evidence considered

No informative pedigree or segregation evidence was retrieved.

Still missing

Family segregation data in affected relatives

Sources

cspec ↗clinvar ↗

BS3 A supplementary ATM functional resource lists this variant as functional with high confidence, but the currently available materials do not provide the criterion-aligned rescue assay details required by the ATM BS3 framework, so BS3 is not applied at this stage. Details ▾Hide ▴

Rule

ATM BS3 requires rescue of ATM-specific function and/or radiosensitivity

Evidence considered

Supplementary table entry classifies p.(Glu2245Lys) as Functional with High confidence.
ATM BS3 requires defined rescue assay evidence.

Still missing

Direct assay details showing rescue of an ATM-specific feature and/or radiosensitivity
Clear mapping of the available functional result to the ATM BS3 rule

Sources

cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951

BP2 No confirmed benign co-occurrence or phase-defined observation with another pathogenic or likely pathogenic ATM variant was identified, so BP2 cannot currently be applied. Details ▾Hide ▴

Rule

ATM BP2 point-based co-occurrence framework

Evidence considered

ATM BP2 uses a point-based co-occurrence framework.

Still missing

Confirmed cis/trans or homozygous co-occurrence data in an unaffected or non-A-T setting

Sources

cspec ↗vcep_atm_pm3_bp2_1_5clinvar ↗

Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis is a missense substitution and is not a nonsense, frameshift, initiation-codon, exon-deletion, or canonical +/-1,2 splice-site variant, so the ATM PVS1 framework does not apply. Details ▾Hide ▴

Rule

ATM PVS1 decision tree for null variants/splice consensus variants

Evidence considered

ATM-specific PVS1 guidance is available.
Variant-level PVS1 assessment places this variant outside generic null-variant buckets.

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_atm_pvs1_1_5

PS1 N/AATM PS1 applies when the same amino acid change is already established by a different nucleotide alteration, but no such comparator was identified for p.(Glu2245Lys); this amino acid change is produced by the observed nucleotide substitution itself. Details ▾Hide ▴

Rule

Same amino acid change as a known pathogenic variant after splicing is ruled out

Evidence considered

ATM PS1 missense rule requires a known pathogenic same-amino-acid comparator.

Sources

cspec ↗vcep_atm_ps1_1_5

PS2 VCEPThe ATM specification marks PS2 as not applicable for this gene framework. Details ▾Hide ▴

Evidence considered

ATM CSPEC/VCEP applicability table