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LYFE SCIENCES
Project: HERA
NM_000051.4:c.7517_7520del
p.Arg2506ThrfsTer3  ·  ATM
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Legacy Engine
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Classification rationale
1

The ATM c.7517_7520del (p.Arg2506ThrfsTer3) variant has been reported in ClinVar as pathogenic and is cataloged by OncoKB as a likely oncogenic loss-of-function alteration.

clinvar ↗ oncokb ↗
2

This variant is rare in population databases, with an overall allele frequency of 5.58e-06 (9/1,612,790 alleles) in gnomAD v4.1 and 7.99e-06 (2/250,380 alleles) in gnomAD v2.1, supporting rarity.

gnomad_v4 ↗ gnomad_v2 ↗
3

No variant-specific functional rescue or loss-of-function assay meeting the ATM VCEP PS3 or BS3 requirements was identified.

cspec ↗ PMID:27413114 ↗ PMID:30348496 ↗ PMID:30553448 ↗
4

This frameshift variant is predicted to truncate ATM at p.Arg2508, and the ATM VCEP framework supports PVS1 for qualifying truncating variants; the ATM CSPEC also allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Arg3047.

cspec ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 7.98786e-06; MAF= 0.00080%, 2/250380 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.27955e-05; MAF= 0.00328%, 1/30492 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 5.58039e-06; MAF= 0.00056%, 9/1612790 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19877e-05; MAF= 0.00220%, 2/90960 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV108796282, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueR2506
Hotspots ↗