This variant is a missense substitution (c.8047A>G, p.Ile2683Val) in ATM, assessed under the ClinGen HBOP VCEP v1.5.0 framework.1 The variant is present in gnomAD v4.1 at a very low frequency (AF=0.00081%, 13/1,613,486 alleles, grpmax FAF=0.0005%), meeting the PM2_Supporting criterion (≤0.001% threshold).2 Computational evidence supports a benign effect: REVEL score of 0.165 (≤0.249 threshold), BayesDel score of -0.311657, and SpliceAI predicts no splicing impact (max delta=0.00, ≤0.1), meeting BP4_Supporting. The VCEP supplementary computational meta-predictor (Suppl_TableS1, PMID 40580951) classifies this variant as Functional with High confidence.3 No functional assay data (kinase activity or radiosensitivity rescue) are available for this variant, so PS3 and BS3 cannot be assessed.4 No case-control studies, segregation data, or trans/homozygous observations in unaffected individuals were identified, leaving PS4, PP1, and BP2 unassessed.5 ClinVar lists this variant as Uncertain significance (3 clinical laboratories) and Likely benign (1 clinical laboratory) with no expert panel submissions.6 Applying the VCEP combining rules: PM2_Supporting (1 pathogenic supporting) and BP4_Supporting (1 benign supporting) yields a classification of Uncertain Significance - Conflicting Evidence per Rule 31.7
ATM
Final classification
Uncertain Significance - Conflicting Evidence
ATM c.8047A>G · p.Ile2683Val
ATM
This variant is a missense substitution (c.8047A>G, p.Ile2683Val) in ATM, assessed under the ClinGen HBOP VCEP v1.5.0 framework.
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 benign; maps to Uncertain Significance - Conflicting Evidence.
Classification rationale
PM2
BP4
Uncertain Significance - Conflicting Evidence
ATM c.8047A>G
PM2 + BP4
→
Uncertain Significance - Conflicting Evidence
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
Population frequency
Overall AF
13 / 1,613,486
0.00081%
Highest · Middle Eastern
0.017%
Homozygotes
0
grpmax FAF
0.0005%
Allele frequency by ancestry — gnomAD v4.1
observed in 2 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Middle Eastern | 1 / 6,060 | 0.017% | 0 |
| European (non-Finnish) | 11 / 1,179,428 | 0.00093% | 0 |
| Admixed American | 0 / 60,022 | — | — |
| European (Finnish) | 0 / 64,032 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,858 | — | — |
| South Asian | 0 / 91,068 | — | — |
| Ashkenazi Jewish | 0 / 29,602 | — | — |
| African/African American | 0 / 75,020 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 8.05709e-06; MAF= 0.00081%, 13/1613486 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165017; MAF= 0.01650%, 1/6060 alleles, homozygotes = 0); grpmax FAF= 5e-06.
Overall AF
2 / 251,274
0.0008%
Highest · European (non-Finnish)
0.0018%
Homozygotes
0
grpmax FAF
0.00029%
Allele frequency by ancestry — gnomAD v2.1
observed in 1 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| European (non-Finnish) | 2 / 113,606 | 0.0018% | 0 |
| African/African American | 0 / 16,254 | — | — |
| Admixed American | 0 / 34,584 | — | — |
| Ashkenazi Jewish | 0 / 10,076 | — | — |
| East Asian | 0 / 18,368 | — | — |
| European (Finnish) | 0 / 21,646 | — | — |
| Remaining individuals | 0 / 6,124 | — | — |
| South Asian | 0 / 30,616 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 7.95944e-06; MAF= 0.00080%, 2/251274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76047e-05; MAF= 0.00176%, 2/113606 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 453719)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.165. BayesDel score = -0.311657.
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.
Literature · 13 PMIDs triaged · 8 high-priority
13papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
28779002 ↗
functional
Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.
Breast cancer (BC) is the most common malignancy in women and has a major heritable component. The risks associated with most rare susceptibility variants are not well estimated. To better characterise the contribution of variants in ATM, CHEK2, PALB2 and XRCC2, we sequenced their coding regions in 13 087 BC cases and 5488 controls from East Anglia, UK. Gene coding regions were enriched via PCR, s
BS3PP5PS3PS4
24418350 ↗
case observation
EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia. This guideline is based on syst
PP5PS4
25394175 ↗
case observation
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.
The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract
PP5PS4
29939840 ↗
case observation
Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.
Purpose To update the formal expert consensus-based guideline recommendations for practicing oncologists and others on the management of brain metastases for patients with human epidermal growth factor receptor 2-positive advanced breast cancer to 2018. Methods An Expert Panel conducted a targeted systematic literature review (for both systemic treatment and CNS metastases) and identified 622 arti
PP5PS4
20050888 ↗
background review
EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PP5PS4
Sources & reference links