Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

ATM c.838A>G

NM_000051.4:c.838A>G (p.Ile280Val) is a missense variant in ATM exon 7. This variant is present in gnomAD v4.1 at extremely low frequency (AF=0.00019%, 3/1,613,222 alleles; grpmax FAF=5.53e-06), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001%.¹ In silico predictions are benign: REVEL score of 0.043 meets the ATM VCEP BP4_Supporting threshold of ≤0.249. SpliceAI predicts no splicing impact (max delta=0.01).² Systematic functional characterization in Suppl_TableS1 (PMID 40580951) classifies this variant as 'Intermediate' (combined score -1.10, confidence medium-high), neither clearly abrogating nor clearly retaining ATM function, insufficient to apply PS3 or BS3 under ATM VCEP rules.³ This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories, ClinVar ID 407462, criteria provided single submitter). No expert panel classification is available.⁴ No pathogenic or likely pathogenic variants at ATM residue Ile280 are reported in ClinVar, and PS1 is not met.⁵

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 gnomad_v4 ↗

2 revelspliceai ↗

3 vcep_suppl_tables1_pmid_40580951

4 clinvar ↗

5 pm5_candidates

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

Present in gnomAD v4.1 at very low frequency (AF=0.00019%, 3/1,613,222 alleles; grpmax FAF=5.53e-06), meeting the ATM VCEP threshold of ≤0.001% for PM2_Supporting. Also present at AF=0.00040% (1/250,510 alleles) in gnomAD v2.1.

gnomAD v4.1: AF 1.86e-063/1613

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

REVEL score of 0.043 meets the ATM VCEP threshold of ≤0.249 for BP4 (Supporting). SpliceAI max delta score of 0.01 further indicates no predicted splicing impact. BayesDel score of -0.435 is also consistent with a benign in silico prediction.

REVEL: 0.043 (threshold ≤0.249)BayesDel: -0.435SpliceAI max delta: 0.01.

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No pathogenic or likely pathogenic variant at ATM residue Ile280 has been identified in ClinVar.

PS3 The systematic functional characterization in the ATM VCEP-supplied Suppl_TableS1 (PMID 40580951) classifies this variant as 'Intermediate' (combined score -1.10, confidence medium-high), neither clearly abrogating nor clearly retaining ATM function.

PS4 No case-control study data available for this variant.

PP1 No segregation data available for this variant.

PP3 REVEL score of 0.043 does not meet the ATM VCEP threshold of >0.7333 for PP3.

Benign

BA1 gnomAD v4.1 grpmax filtering allele frequency of 5.53e-06 does not meet the ATM VCEP BA1 threshold of >0.5%.

BS1 gnomAD v4.1 grpmax filtering allele frequency of 5.53e-06 does not meet the ATM VCEP BS1 threshold of >0.05%.

BS3 The systematic functional characterization in the ATM VCEP-supplied Suppl_TableS1 (PMID 40580951) classifies this variant as 'Intermediate' (combined score -1.10), not 'Functional.' This does not meet the ATM VCEP BS3 requirement of demonstrated rescue of ATM-specific features (supporting) or both ATM-specific features and radiosensitivity (moderate).

BP2 No evidence of co-occurrence in trans with a pathogenic variant in unaffected individuals available for BP2 assessment.

N/A · 17 PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85963e-06; MAF= 0.00019%, 3/1613222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.333e-05; MAF= 0.00333%, 2/60006 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.99186e-06; MAF= 0.00040%, 1/250510 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.8967e-05; MAF= 0.00290%, 1/34522 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 / 1,613,222
0 hom · FAF 0.00055%

Admixed American 2 / 60,006	0.0033%
European (non-Finnish) 1 / 1,179,796	8.5e-05%

+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0004% · 1 / 250,510
0 hom

Admixed American

1 / 34,522

0.0029%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-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 (6 clinical laboratories). (ClinVarID = 407462)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.043. BayesDel score = -0.43543.

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

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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

32761968 ↗ Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer. CLINVAR

34262154 ↗ Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia. 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

35534704 ↗ The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. CLINVAR

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

Re-run this variant?