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.1 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.2 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 BS3.3 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.4
ATM
Final classification
Uncertain Significance - Conflicting Evidence
ATM c.6733G>A · p.Glu2245Lys
ATM
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.
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.
Classification rationale
PM2
BP4
Uncertain Significance - Conflicting Evidence
ATM c.6733G>A
PM2 + BP4
→
Uncertain Significance - Conflicting Evidence
3
vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1cspec ↗
4
revelspliceai ↗bayesdelcspec ↗
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 9 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
review
Pathogenic
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.
gnomAD v4.1 total AF 6.1972e-07gnomAD v4.1 highest subpopulation AF 8.4753e-07Absent from gnomAD v2.1
✓
BP4
supporting
review
Benign
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.
REVEL 0.076SpliceAI max delta 0.02BayesDel -0.479783
Assessed · not applied
Pathogenic
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.
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.
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.
PP1
No segregation data were identified for this variant, so PP1 cannot currently be applied.
PP3
Available computational evidence does not support a damaging effect.
Benign
BA1
Population frequency does not meet the ATM BA1 threshold.
BS1
Population frequency does not meet the ATM BS1 threshold.
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.
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.
N/A · 17
PVS1 · PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.1972e-07; MAF= 0.00006%, 1/1613632 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47531e-07; MAF= 0.00008%, 1/1179898 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,632
0 hom
0 hom
European (non-Finnish) 1 / 1,179,898 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1484028)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.076. BayesDel score = -0.479783.
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99589774, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 6 PMIDs not cited in assessment
24418350 ↗
EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
CLINVAR
25394175 ↗
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.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR