LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-25
Case ID: NM_000051.4_c.6733G_A_20260525_200708
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.6733G>A

ATM  · NP_000042.3:p.(Glu2245Lys)  · NM_000051.4
GRCh37: chr11:108196197 G>A  ·  GRCh38: chr11:108325470 G>A
Gene: ATM Transcript: NM_000051.4
Final call
PM2 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Glu2245Lys)
gnomAD AF
6.197199857216516e-07 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
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.
3
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.
4
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.
Final determination: Rule31 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Uncertain Significance - Conflicting Evidence.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A This 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.
cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1 N/A ATM 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.
cspec vcep_atm_ps1_1_5
PS2 N/A The ATM specification marks PS2 as not applicable for this gene framework.
cspec
PS3 Not assessed 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.
cspec vcep_atm_pvs1_1_5 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4 Not assessed 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.
cspec clinvar oncokb
PM1 N/A The ATM specification marks PM1 as not applicable for this gene framework.
cspec
PM2 Met 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.
cspec gnomad_v4 gnomad_v2 gnomad_canada
PM3 Not assessed 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.
cspec vcep_atm_pm3_bp2_1_5 clinvar
PM4 N/A ATM PM4 is specified for stop-loss variants, and this variant is a missense substitution.
cspec
PM5 N/A In the ATM specification, PM5 is not classic same-residue missense logic. It is reserved for truncating or qualifying splice variants upstream of p.Arg3047, so this missense variant does not meet the governing PM5 rule.
cspec pm5_candidates
PM6 N/A The ATM specification marks PM6 as not applicable for this gene framework.
cspec
PP1 Not assessed No segregation data were identified for this variant, so PP1 cannot currently be applied.
cspec clinvar
PP2 N/A The ATM specification marks PP2 as not applicable for this gene framework.
cspec
PP3 Not met 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.
cspec revel spliceai bayesdel
PP4 N/A The ATM specification marks PP4 as not applicable for this gene framework.
cspec
PP5 N/A The ATM specification marks PP5 as not applicable for this gene framework.
cspec
BA1 Not met 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%.
cspec gnomad_v4
BS1 Not met 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%.
cspec gnomad_v4
BS2 N/A The ATM specification marks BS2 as not applicable for this gene framework.
cspec
BS3 Not assessed 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.
cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4 N/A The ATM specification marks BS4 as not applicable for this gene framework.
cspec
BP1 N/A The ATM specification marks BP1 as not applicable for this gene framework.
cspec
BP2 Not assessed 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.
cspec vcep_atm_pm3_bp2_1_5 clinvar
BP3 N/A The ATM specification marks BP3 as not applicable for this gene framework.
cspec
BP4 Met 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.
cspec revel spliceai bayesdel
BP5 N/A The ATM specification marks BP5 as not applicable for this gene framework.
cspec
BP6 N/A The ATM specification marks BP6 as not applicable for this gene framework.
cspec
BP7 N/A ATM BP7 is specified for synonymous and deep intronic variants or for RNA evidence showing no splice defect, and this variant is a missense substitution.
cspec
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