Classification rationale

PP3 Likely Pathogenic

ATM c.3137T>C

The ATM c.3137T>C (p.Leu1046Pro) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles; 0 homozygotes), with the highest observed frequency in the South Asian population at 2.19587e-05 (2/91080 alleles; 0 homozygotes).² In silico evidence supports a deleterious missense effect, with REVEL 0.854 exceeding the ATM PP3 threshold of 0.7333, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).³

PP3 → Likely Pathogenic

1 evidence.json:cosmicevidence.json:clinvar

2 evidence.json:gnomad

3 prefetch.json:revelevidence.json:spliceaicase_summary.json:cspec

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 11 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 · 1

Strength Supporting Moderate Strong Very strong

PP3 Supporting review Pathogenic

In silico evidence supports a deleterious missense effect: the REVEL score is 0.854, which is above the ATM PP3 threshold of 0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.

REVEL 0.854ATM PP3 threshold >0.7333SpliceAI max delta score 0.01

Assessed · not applied · 5 not met · 6 not assessed

Pathogenic

PS1 No pathogenic or likely pathogenic ATM variant producing the same amino acid change was identified in the available disease databases or ATM PS1 materials, so PS1 is not met.

PS3 No variant-specific ATM functional study was identified showing failure to rescue both an ATM-specific function and radiosensitivity, so PS3 was not assessed.

PS4 No case-control data or statistically significant enrichment data for this variant were identified, so PS4 was not assessed.

PM2 This variant is absent from gnomAD v2.1 and is very rare in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles), but the highest observed South Asian frequency is 2.19587e-05 (0.00220%; 2/91080), which is above the ATM PM2_Supporting threshold of 0.001%, so PM2 was not applied.

PM3 No observations of this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 was not assessed.

PP1 No segregation data were identified for this variant, so PP1 was not assessed.

Benign

BA1 The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), which is below the ATM BA1 threshold of 0.5%, so BA1 is not met.

BS1 The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), which is below the ATM BS1 threshold of 0.05%, so BS1 is not met.

BS3 No variant-specific ATM functional study was identified showing rescue of ATM-specific function or radiosensitivity, so BS3 was not assessed.

BP2 No co-occurrence data were identified showing this variant in trans with a pathogenic ATM variant in an unaffected non-ataxia-telangiectasia setting, so BP2 was not assessed.

BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splicing threshold of 0.1, but the REVEL score is 0.854, which is above the ATM BP4 missense threshold of 0.249, so BP4 is not met.

N/A · 16 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85893e-06; MAF= 0.00019%, 3/1613832 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19587e-05; MAF= 0.00220%, 2/91080 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,613,832
0 hom · FAF 0.00037%

South Asian 2 / 91,080	0.0022%
European (non-Finnish) 1 / 1,179,776	8.5e-05%

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

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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

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