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 ↗

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

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