Classification rationale

PM2 BP4 Uncertain Significance - Conflicting Evidence

ATM c.2207C>T

The ATM c.2207C>T (p.Ala736Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance by 4 clinical laboratories.¹ The variant is present at very low frequency in gnomAD, including 3 of 1458952 alleles in v4.1 with no homozygotes, which supports PM2_Supporting and is well below the ATM BS1 and BA1 frequency thresholds.² In silico evidence argues against a deleterious effect: REVEL is 0.103 and SpliceAI shows a maximum delta score of 0.02, supporting BP4 and arguing against PP3.³

PM2 + BP4 → Uncertain Significance - Conflicting Evidence

1 cosmicclinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 revelspliceai ↗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 · 2 applied · 10 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

PM2 supporting review Pathogenic

The variant is present at extremely low frequency in gnomAD v4.1 (3/1,458,952 alleles; AF 2.05627e-06; no homozygotes), which is below the ATM VCEP PM2_Supporting threshold of ≤0.001%.

gnomAD v4.1 total AF 2.05627e-06; 3/1458952 alleles; homozygotes 0.gnomAD v2.1 total AF 7.96223e-06; 2/251186 alleles; homozygotes 0.

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

BP4 supporting review Benign

In silico evidence supports a benign interpretation: the REVEL score is 0.103, which is at or below the ATM VCEP BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a max delta score of 0.02, below the BP4 splicing threshold of ≤0.1.

REVEL score 0.103.SpliceAI DS_AG 0.0, DS_AL 0.02, DS_DG 0.0, DS_DL 0.01; max delta score 0.02.

spliceai ↗cspec ↗

Assessed · not applied · 3 not met · 7 not assessed

Pathogenic

PS1 No established pathogenic or likely pathogenic reference variant producing the same amino acid change or the same splice event was identified from the available sources, so PS1 was not applied.

PS3 No ATM-specific functional assay evidence showing failure to rescue an ATM-specific feature or radiosensitivity was identified for this variant, so PS3 was not applied.

PS4 No case-control evidence meeting the ATM VCEP PS4 threshold was identified, and the available ClinVar observation does not establish statistical enrichment in affected individuals.

PM3 No evidence was identified that this variant was observed in trans with a pathogenic ATM variant in affected individuals under the ATM PM3/BP2 point system, so PM3 was not applied.

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

PP3 The missense REVEL score is 0.103, which is well below the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI predicts no significant splice impact (max delta score 0.02), so PP3 is not met.

Benign

BA1 The highest observed gnomAD v4.1 filtering allele frequency is far below the ATM VCEP BA1 threshold of >0.5%, so BA1 is not met.

BS1 The gnomAD v4.1 frequency is far below the ATM VCEP BS1 threshold of >0.05%, so BS1 is not met.

BS3 No ATM-specific functional assay evidence showing rescue of an ATM-specific feature or radiosensitivity was identified for this variant, so BS3 was not applied.

BP2 No evidence was identified that this variant co-occurred in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual under the ATM PM3/BP2 point system, so BP2 was not applied.

N/A · 16 PVS1 · PS2 · PM1 · 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= 2.05627e-06; MAF= 0.00021%, 3/1458952 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.70245e-06; MAF= 0.00027%, 3/1110104 alleles, homozygotes = 0); grpmax FAF= 7.2e-07.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.96223e-06; MAF= 0.00080%, 2/251186 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.76013e-05; MAF= 0.00176%, 2/113628 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00021% · 3 / 1,458,952
0 hom · FAF 7.2e-05%

European (non-Finnish)

3 / 1,110,104

0.00027%

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

gnomAD v2.1

0.0008% · 2 / 251,186
0 hom · FAF 0.00029%

European (non-Finnish)

2 / 113,628

0.0018%

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

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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.

Hotspots ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

Cancer hotspots

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