The variant NM_000051.4:c.2522A>C (p.Asp841Ala) is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.1156% (127 alleles, including 3 homozygotes), exceeding the ATM VCEP BS1_Strong threshold of >0.05%. This population frequency is incompatible with a highly penetrant pathogenic ATM variant.1 Computational predictors are consistent with a benign effect: REVEL score is 0.139 (below the BP4_Supporting threshold of ≤0.249), SpliceAI predicts no splice impact (max delta = 0.00), and BayesDel score is -0.415893 (benign range).2 The VCEP ATM functional scoring table (Suppl_TableS1, PMID 40580951) classifies D841A as 'Functional' with high confidence, placing it in the non-damaging category among ATM missense variants.3 No variant-specific functional evidence supporting pathogenicity was identified in the literature; six full-text papers were reviewed and none mention this variant.
ATM
Final classification
Likely Benign
BS1BP4
ATM
c.2522A>C
p.Asp841Ala
This variant
The variant NM_000051.4:c.2522A>C (p.Asp841Ala) is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.1156% (127 alleles, including 3 homozygotes), exceeding the ATM VCEP BS1_Strong threshold of >0.05%. This population frequency is incompatible with a highly penetrant pathogenic ATM variant.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP4 supporting; maps to Likely Benign.
Classification rationale
BS1BP4
Likely Benign
ATM c.2522A>C
BS1 + BP4
→
Likely Benign
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
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
ATM VCEP BS1_Strong is met: grpmax filtering allele frequency in gnomAD v4.1 is 0.1156%, exceeding the >0.05% threshold. The variant is present in 127 alleles including 3 homozygotes in v4.1, and 43 alleles including 1 homozygote in v2.1, with highest frequency in the South Asian population (v4.1 AF=0.135%). This population frequency is incompatible with a highly penetrant pathogenic ATM variant.
gnomAD v4.1 grpmax FAF = 0.1156% (> 0.05% VCEP BS1_Strong threshold)3 homozygotes in v4.11 homozygote in v2.1
✓
BP4
supporting
Benign
ATM VCEP BP4_Supporting for missense variants is met: REVEL score is 0.139, which is ≤0.249. Additionally, SpliceAI predicts no splice impact (max delta = 0.00, ≤0.1), and BayesDel score is -0.415893 (benign range). Multiple computational lines of evidence suggest no deleterious effect.
REVEL = 0.139 (≤ 0.249 threshold)SpliceAI max delta = 0.00BayesDel = -0.415893 (benign)
Assessed · not applied
· 7 not met · 2 not assessed
Pathogenic
PS1
PS1 requires a previously established pathogenic missense change at the same residue.
PS3
No variant-specific functional studies were identified for NM_000051.4:c.2522A>C (p.Asp841Ala) in the literature reviewed.
PS4
PS4 requires case-control studies demonstrating significant enrichment in affected individuals.
PM2
ATM VCEP PM2_Supporting requires allele frequency ≤0.001% in gnomAD v4.
PP1
No segregation data are available for this variant.
PP3
ATM VCEP PP3_Supporting for missense variants requires REVEL score >0.7333.
Benign
BA1
ATM VCEP BA1 requires grpmax filtering allele frequency >0.5% in gnomAD v4.
BS3
No variant-specific benign functional evidence was identified.
BP2
BP2 requires proband data evaluated through the ATM PM3/BP2 point table.
N/A · 15
PVS1 · PS2 · PM1 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 7.86781e-05; MAF= 0.00787%, 127/1614172 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00135037; MAF= 0.13504%, 123/91086 alleles, homozygotes = 3); grpmax FAF= 0.00115569.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000171039; MAF= 0.01710%, 43/251404 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00137201; MAF= 0.13720%, 42/30612 alleles, homozygotes = 1); grpmax FAF= 0.00104332.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0079%
· 127 / 1,614,172
3 hom · FAF 0.12%
3 hom · FAF 0.12%
South Asian 123 / 91,086 |
0.14% 3 hom |
Remaining individuals 4 / 62,506 |
0.0064% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.017%
· 43 / 251,404
1 hom · FAF 0.1%
1 hom · FAF 0.1%
South Asian 42 / 30,612 |
0.14% 1 hom |
Remaining individuals 1 / 6,138 |
0.016% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Uncertain significance (5 clinical laboratories). (ClinVarID = 184552)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.139. BayesDel score = -0.415893.
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 · 9 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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
26689913 ↗
Patterns and functional implications of rare germline variants across 12 cancer types.
CLINVAR
33552952 ↗
Mutational Landscape for Indian Hereditary Breast and Ovarian Cancer Cohort Suggests Need for Identifying Population Specific Genes and Biomarkers for Screening.
CLINVAR
34242744 ↗
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
CLINVAR
34326862 ↗
Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.
CLINVAR
17508274 ↗
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
CLINVAR
24366402 ↗
Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR