Classification rationale

PP3 VUS

ATM c.8418+5_8418+8del

The ATM c.8418+5_8418+8del (NP_000042.3:p.?) variant has not been reported in ClinVar.¹ This variant is present in gnomAD v4.1 at AF 0.00465% (75/1,613,598 alleles; grpmax FAF 0.005111%) and in gnomAD v2.1 at AF 0.00071% (2/282,394 alleles), which is above the ATM PM2_Supporting threshold of 0.001% and below the BS1 threshold of 0.05%.² SpliceAI predicts an adverse splicing effect with a maximum delta score of 0.89, which exceeds the ATM PP3 threshold of 0.2 for intronic variants outside the donor ±1,2 positions and supports PP3.³

PP3 → VUS

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗cspec ↗

3 spliceai ↗cspec ↗

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

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 1 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= 4.648e-05; MAF= 0.00465%, 75/1613598 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.27221e-05; MAF= 0.00627%, 74/1179808 alleles, homozygotes = 0); grpmax FAF= 5.111e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.0823e-06; MAF= 0.00071%, 2/282394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.55222e-05; MAF= 0.00155%, 2/128848 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0046% · 75 / 1,613,598
0 hom · FAF 0.0051%

European (non-Finnish) 74 / 1,179,808	0.0063%
African/African American 1 / 74,856	0.0013%

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

gnomAD v2.1

0.00071% · 2 / 282,394
0 hom

European (non-Finnish)

2 / 128,848

0.0016%

+ 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 is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.89).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC