Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

ATM c.8047A>G

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

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 cspec ↗

2 gnomad_v4 ↗cspec ↗

3 revelspliceai ↗bayesdelvcep_suppl_tables1_pmid_40580951cspec ↗

4 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1cspec ↗

5 cspec ↗

6 clinvar ↗

7 final_classification_frameworkcspec ↗

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 Pathogenic

This variant has a frequency of 0.00081% (8.06e-06, 13/1,613,486 alleles) in gnomAD v4.1, which is ≤0.001% meeting the ATM VCEP threshold for PM2_Supporting. The VCEP specifies PM2 should be applied at supporting strength only (not moderate).

gnomAD v4.1 AF = 8.06e-06 (0.00081%)13/1613

gnomad_v4 ↗cspec ↗

✓

BP4 supporting Benign

This missense variant has a REVEL score of 0.165, which is ≤0.249, meeting the ATM VCEP BP4 threshold for missense variants. Additionally, SpliceAI predicts no splicing impact (max delta score = 0.00, which is ≤0.1), satisfying the splicing component. The VCEP supplementary table (Suppl_TableS1, PMID 40580951) also classifies this variant as 'Functional' (combined score -0.265, High confidence). BayesDel score of -0.311657 further supports a benign computational prediction.

REVEL = 0.165 (≤0.249)SpliceAI max delta = 0.00 (≤0.1)BayesDel = -0.311657

spliceai ↗cspec ↗

Assessed · not applied

Pathogenic

PS1 PS1 requires a different nucleotide change producing the same amino acid change (Ile2683Val) that has been established as pathogenic.

PS3 No well-established functional assay data are available for this variant.

PS4 No case-control study with a p-value ≤0.05 and an odds ratio/relative risk ≥2 (or lower 95% CI ≥1.5) has been identified for this specific variant.

PP1 The ATM VCEP restricts PP1 to autosomal recessive (A-T) conditions where affected relatives must have both variants identified in the proband.

PP3 For missense variants, the ATM VCEP requires a REVEL score >0.7333 to apply PP3.

Benign

BA1 The ATM VCEP requires a grpmax filtering allele frequency >0.5% in gnomAD v4 for BA1.

BS1 The ATM VCEP requires a grpmax filtering allele frequency >0.05% in gnomAD v4 for BS1.

BS3 No functional assay data are available showing that this variant rescues either ATM-specific features (e.g., phosphorylation of ATM-specific targets) or radiosensitivity.

BP2 The ATM VCEP applies BP2 through the PM3/BP2 point table for observations of the variant in trans with a pathogenic variant or in homozygous state in unaffected individuals (≥18 years, no evidence of A-T).

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= 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.

v2.1

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.

🇨🇦 CA

This variant is absent from gnomAD-Canada.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00081% · 13 / 1,613,486
0 hom · FAF 0.0005%

Middle Eastern 1 / 6,060	0.017%
Remaining individuals 1 / 62,484	0.0016%
European (non-Finnish) 11 / 1,179,428	0.00093%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0008% · 2 / 251,274
0 hom · FAF 0.00029%

European (non-Finnish)

2 / 113,606

0.0018%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 453719)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.165. BayesDel score = -0.311657.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 10 PMIDs not cited in assessment

28779002 ↗ Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. CLINVAR

20301317 ↗ Hereditary Ataxia Overview. CLINVAR

20301790 ↗ Ataxia-Telangiectasia. CLINVAR

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

26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

29939840 ↗ 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. CLINVAR

20050888 ↗ EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Re-run this variant?