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.1 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.2 No variant-specific functional rescue or loss-of-function assay meeting the ATM VCEP PS3 or BS3 requirements was identified.3 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.Arg3047.4
Final classification
Pathogenic
PVS1PM2PM5
ATM
c.7517_7520del
p.Arg2506ThrfsTer3
This variant
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.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework; Rule4 applies.
Classification rationale
PVS1PM2PM5
Pathogenic
ATM c.7517_7520del
PVS1 + PM2 + PM5
→
Pathogenic
4
cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_a_t_m___p_v_s_1___1___5
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 · 3 applied · 9 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 · 3
Strength
Supporting
Moderate
Strong
Very strong
PVS1
very strong
review
Pathogenic
This variant is a frameshift change predicted to truncate ATM as p.(Arg2506ThrfsTer3). ATM loss of function is an established disease mechanism in the ATM VCEP framework, and this truncating event is not at the extreme 3' end, supporting full-strength PVS1.
Frameshift consequence: p.(Arg2506ThrfsTer3)ATM is eligible for PVS1 in the official ATM VCEP frameworkATM PVS1 guidance indicates PVS1 can be applied for qualifying truncating variants
PM2
supporting
review
Pathogenic
This variant is rare in population databases. In gnomAD v4.1 the overall allele frequency is 5.58e-06 (0.000558%; 9/1,612,790 alleles), which is below the ATM PM2_Supporting threshold of 0.001%, and no homozygotes were reported.
gnomAD v4.1 overall AF 5.580391743500393e-06 (9/1612790)homozygotes 0gnomAD v2.1 overall AF 7.987858455148174e-06 (2/250380)
PM5
supporting
review
Pathogenic
The ATM CSPEC allows PM5 at supporting strength for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant is predicted to truncate the protein at p.Arg2508, which is upstream of p.Arg3047, so PM5_Supporting is met.
Variant is a truncating frameshiftPredicted stop occurs at p.Arg2508upstream of p.Arg3047
Assessed · not applied
· 3 not met · 6 not assessed
Pathogenic
PS3
No variant-specific functional study was identified that shows failure to rescue an ATM-specific function in a manner meeting the ATM VCEP PS3 rules.
PS4
This variant has been reported in affected individuals and is listed in ClinVar, but no ATM-specific case-control study was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥2 or lower 95% confidence interval ≥1.5, so PS4 is not met.
PM3
Published reports indicate this variant has been observed in individuals with ataxia-telangiectasia, but the available evidence reviewed here does not provide enough case-level phase and scoring detail to assign ATM PM3 points confidently.
PP1
No segregation data were identified that document this variant segregating with recessive ATM-related disease in the number of affected relatives required by the ATM VCEP PP1 rules.
Benign
BA1
The gnomAD v4.1 filtering allele frequency is 3.65e-06 (0.000365%), which is well below the ATM BA1 threshold of >0.5%, so BA1 is not met.
BS1
The gnomAD v4.1 filtering allele frequency is 3.65e-06 (0.000365%), which is well below the ATM BS1 threshold of >0.05%, so BS1 is not met.
BS3
No variant-specific functional study was identified showing rescue of ATM-specific function or radiosensitivity in a manner meeting the ATM VCEP BS3 rules.
BS4
No non-segregation evidence was identified for this variant in families studied for ATM-related disease.
BP2
No evidence was identified showing this variant in trans with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual, so ATM BP2 points could not be assigned.
N/A · 16
PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · PP5 · BS2 · BP1 · BP3 · BP4 · 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= 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.
v2.1
This 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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00056%
· 9 / 1,612,790
0 hom · FAF 0.00037%
0 hom · FAF 0.00037%
South Asian 2 / 90,960 |
0.0022% |
European (non-Finnish) 7 / 1,179,424 |
0.00059% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 250,380
0 hom
0 hom
South Asian 1 / 30,492 |
0.0033% |
European (non-Finnish) 1 / 113,310 |
0.00088% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 1.00).
Functional
Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Loss-of-function.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
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).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links