LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-21
Case ID: NM_000051.4_c.7517_7520del_20260421_153811
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.7517_7520del

ATM  · NP_000042.3:p.(Arg2506ThrfsTer3)  · NM_000051.4
GRCh37: chr11:108202168 TAGAG>T  ·  GRCh38: chr11:108331441 TAGAG>T
Gene: ATM Transcript: NM_000051.4
Final call
Pathogenic
PVS1_Very_Strong PM2_Supporting PM5_Supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Arg2506ThrfsTer3)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
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.
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.
3
No variant-specific functional rescue or loss-of-function assay meeting the ATM VCEP PS3 or BS3 requirements was identified.
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.
Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 Met 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.
cspec pvs1_gene_context pvs1_variant_assessment vcep_a_t_m___p_v_s_1___1___5
PS1 N/A PS1 is intended for the same amino acid change as an established pathogenic variant or for specific splice events with matching reference variants. This frameshift deletion does not meet those circumstances.
cspec vcep_a_t_m___p_s_1___1___5
PS2 N/A The ATM VCEP marks PS2 as not applicable for this gene specification.
cspec
PS3 Not assessed 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.
cspec PMID:27413114 PMID:30348496 PMID:30553448
PS4 Not met 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.
cspec clinvar PMID:12815592 PMID:15039971 PMID:16941484 PMID:17124347 PMID:19691550
PM1 N/A The ATM VCEP marks PM1 as not applicable for this gene specification.
cspec
PM2 Met 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.
cspec gnomad_v4 gnomad_v2
PM3 Not assessed 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.
cspec vcep_a_t_m___p_m_3___b_p_2___1___5 clinvar PMID:12815592 PMID:15039971 PMID:16941484 PMID:17124347 PMID:19691550
PM4 N/A ATM PM4 is specified for stop-loss variants. This variant is a frameshift deletion, so PM4 does not apply.
cspec
PM5 Met 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.
cspec pvs1_variant_assessment
PM6 N/A The ATM VCEP marks PM6 as not applicable for this gene specification.
cspec
PP1 Not assessed 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.
cspec PMID:12815592 PMID:19691550
PP2 N/A The ATM VCEP marks PP2 as not applicable for this gene specification.
cspec
PP3 N/A ATM PP3 is specified for missense variants and certain non-canonical splice-related variants. This exonic frameshift deletion is evaluated primarily under PVS1 rather than PP3.
cspec spliceai pvs1_variant_assessment
PP4 N/A The ATM VCEP marks PP4 as not applicable for this gene specification.
cspec
PP5 N/A The ATM VCEP marks PP5 as not applicable for this gene specification.
cspec
BA1 Not met 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.
cspec gnomad_v4
BS1 Not met 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.
cspec gnomad_v4
BS2 N/A The ATM VCEP marks BS2 as not applicable for this gene specification.
cspec
BS3 Not assessed No variant-specific functional study was identified showing rescue of ATM-specific function or radiosensitivity in a manner meeting the ATM VCEP BS3 rules.
cspec PMID:27413114 PMID:30348496 PMID:30553448
BS4 Not assessed No non-segregation evidence was identified for this variant in families studied for ATM-related disease.
cspec PMID:12815592 PMID:19691550
BP1 N/A The ATM VCEP marks BP1 as not applicable for this gene specification.
cspec
BP2 Not assessed 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.
cspec vcep_a_t_m___p_m_3___b_p_2___1___5 clinvar
BP3 N/A The ATM VCEP marks BP3 as not applicable for this gene specification.
cspec
BP4 N/A ATM BP4 is specified for missense variants or variants with no predicted splice impact. This frameshift deletion is not that variant class and also has SpliceAI max delta score 1.00 rather than ≤0.1.
cspec spliceai
BP5 N/A The ATM VCEP marks BP5 as not applicable for this gene specification.
cspec
BP6 N/A The ATM VCEP marks BP6 as not applicable for this gene specification.
cspec
BP7 N/A ATM BP7 is specified for synonymous and deep intronic variants or for RNA studies showing no aberrant splicing. This variant is an exonic frameshift deletion, so BP7 does not apply.
cspec
Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.