NM_000051.4:c.4997A>C (p.Glu1666Ala) is a missense variant at an extremely low population frequency (gnomAD v4.1 AF = 1.86e-06, 3/1,613,480 alleles).1 Functional assay data curated by the ClinGen HBOP VCEP demonstrate that p.Glu1666Ala rescues both ATM kinase activity and cellular radiosensitivity to wild-type levels, consistent with a benign functional effect (BS3_Moderate).2 Multiple in silico predictors support a benign effect: REVEL 0.054 (≤0.249, BP4_Supporting), BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033.3 SpliceAI predicts a possible splicing impact (max delta 0.24, ≥0.2) qualifying for PP3_Supporting under the VCEP splicing prediction rule, though this is modestly above threshold and conflicts with the benign in silico and functional evidence.4 The variant is absent from COSMIC and no case-control or segregation studies are available. Six publications provided by ClinVar were reviewed in full text; none mention NM_000051.4:c.4997A>C specifically.5
ATM
Final classification
Uncertain Significance - Conflicting Evidence
ATM c.4997A>C · p.Glu1666Ala
ATM
NM_000051.4:c.4997A>C (p.Glu1666Ala) is a missense variant at an extremely low population frequency (gnomAD v4.1 AF = 1.86e-06, 3/1,613,480 alleles).
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 v1.5 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, PP3 supporting, BS3 moderate, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2PP3
BS3BP4
Uncertain Significance - Conflicting Evidence
ATM c.4997A>C
PM2 + PP3 + BS3 + BP4
→
Uncertain Significance - Conflicting Evidence
2
vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
3
revelbayesdel
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 4 applied · 7 assessed
Applied · 4
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present in gnomAD v4.1 at an extremely low frequency (AF=1.86e-06; 3/1,613,480 alleles, 0 homozygotes; grpmax FAF=6.8e-07). Per ATM VCEP v1.5, frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting.
gnomAD v4.1 AF = 1.86e-06 (0.000186%)≤0.001% threshold met3 alleles in 1
✓
PP3
supporting
Pathogenic
SpliceAI predicts a possible splicing impact (max delta score = 0.24). Per ATM VCEP v1.5, SpliceAI ≥0.2 qualifies for PP3_Supporting for missense variants via the splicing prediction route. The REVEL score (0.054) does NOT independently support PP3 via the missense pathway (threshold >0.7333).
SpliceAI max delta = 0.24≥0.2 threshold for splicing prediction metREVEL 0.054 does not meet missense threshold (>0.7333).
✓
BS3
moderate
Benign
Functional assay data curated by the ATM HBOP VCEP (Suppl_TableS1, based on kinase activity assays: Mitui 2009 PMID 18634022, Barone 2009 PMID 19431188; and radiosensitivity assays: Mitui 2009, Scott 2002 PMID 11805335) classify NM_000051.4:c.4997A>C (p.E1666A) as 'Functional' with High confidence (combined score 0.456). The variant rescues both ATM-specific kinase activity (phosphorylation of ATM targets) and cellular radiosensitivity, satisfying the VCEP BS3_Moderate threshold: variant rescues both an ATM-specific feature AND radiosensitivity.
VCEP functional data: E1666A classified as 'Functional' (High confidence)rescues ATM kinase activity (Mitui 2009Barone 2009) and radiosensitivity (Mitui 2009
✓
BP4
supporting
Benign
The REVEL score for this variant is 0.054, which is ≤0.249, meeting the ATM VCEP BP4_Supporting threshold for missense variants. Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033. The SpliceAI delta (0.24) does NOT support BP4 via the splicing route (threshold ≤0.1).
REVEL = 0.054 (≤0.249)BayesDel = -0.367EVE = 0.058
Assessed · not applied
Pathogenic
PS1
PS1 requires a (likely) pathogenic variant at the same nucleotide position with a different nucleotide change.
PS3
PS3 requires experimental evidence of a damaging effect on ATM function.
PS4
The ATM VCEP requires case-control studies with p-value ≤0.05 AND (OR/HR/RR ≥2 OR lower 95% CI ≥1.5) for PS4.
PP1
The ATM VCEP applies PP1 only for autosomal recessive (ataxia telangiectasia) conditions, requiring segregation in affected relatives.
Benign
BA1
The ATM VCEP BA1 threshold is grpmax Filtering AF >0.5% in gnomAD v4.
BS1
The ATM VCEP BS1 threshold is grpmax Filtering AF >0.05% in gnomAD v4.
BP2
BP2 requires observation of the variant in trans with a P/LP variant in an unaffected individual (≥18 years, no evidence of A-T) or homozygous in an unaffected individual per the ATM PM3/BP2 table.
N/A · 14
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85934e-06; MAF= 0.00019%, 3/1613480 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54327e-06; MAF= 0.00025%, 3/1179586 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48172e-05; MAF= 0.00648%, 1/15428 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,613,480
0 hom · FAF 6.8e-05%
0 hom · FAF 6.8e-05%
European (non-Finnish) 3 / 1,179,586 |
0.00025% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0032%
· 1 / 31,396
0 hom
0 hom
European (non-Finnish) 1 / 15,428 |
0.0065% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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 (4 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 1043495)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.24). REVEL score = 0.054. BayesDel score = -0.367169.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 6 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
24366376 ↗
Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
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