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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
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