LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-10
Case ID: NM_000051.4_c.8052_8055delGTCA_20260510_020454
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.8052_8055delGTCA

ATM  · NP_000042.3:p.(Gln2684HisfsTer8)  · NM_000051.4
GRCh37: chr11:108205734 ACAGT>A  ·  GRCh38: chr11:108335007 ACAGT>A
Gene: ATM Transcript: NM_000051.4
Final call
Pathogenic
PVS1 very strong PM5 supporting PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Gln2684HisfsTer8)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The ATM c.8052_8055del (p.Gln2684HisfsTer8; p.Q2684Hfs*8) variant has not been observed in somatic cancers in COSMIC and is reported in ClinVar as pathogenic.
2
This variant is absent from gnomAD v2.1 and v4.1, which is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4 and does not meet the BS1 (>0.05%) or BA1 (>0.5%) population thresholds.
3
This 4-bp deletion causes a frameshift in exon 55 with a premature stop codon, and under the ATM VCEP framework that supports PVS1 at very strong strength; because the predicted stop is upstream of p.Arg3047, it also meets the ATM-specific truncation-based PM5 rule.
4
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, and the ATM PP3/BP4 computational rules are not applied to this exonic frameshift variant class.
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 4-bp deletion causes a frameshift, p.Gln2684HisfsTer8 (p.Q2684Hfs*8), in exon 55 of ATM. In the ATM VCEP framework, loss of function is an established disease mechanism, the reference transcript exons are considered constitutive, and this premature stop is well upstream of the transcript end rather than at the extreme 3′ end, supporting PVS1 at very strong strength.
cspec vcep_atm_pvs1_1_5 pvs1_gene_context pvs1_variant_assessment
PM5 Met ATM repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a premature stop at p.Gln2691, which is upstream of p.Arg3047, so ATM-specific PM5_Supporting is met; classic same-residue missense comparator logic is not required for this gene-specific rule.
cspec pm5_candidates
PM2 Met This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. An observed frequency of 0 is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4, so PM2_Supporting is met.
cspec gnomad_v4 gnomad_v2
BA1 Not met This variant is absent from gnomAD v4.1. An observed frequency of 0 is below the ATM BA1 threshold of >0.5%, so BA1 is not met.
cspec gnomad_v4
BS1 Not met This variant is absent from gnomAD v4.1. An observed frequency of 0 is below the ATM BS1 threshold of >0.05%, so BS1 is not met.
cspec gnomad_v4
PS4 Not met This variant has been reported in ClinVar and cited literature, but no case-control study or exact-variant enrichment analysis was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥2, or a lower 95% confidence interval ≥1.5. Therefore PS4 is not met.
cspec clinvar PMID:23807571 PMID:25614872
PM3 Not assessed No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an affected individual was identified, so PM3 cannot be assigned from the available evidence.
vcep_atm_pm3_bp2_1_5 clinvar
BP2 Not assessed No evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected individual, with phase unknown in an unaffected individual, or as a qualifying homozygous finding under the ATM BP2 framework. Therefore BP2 is not assigned.
vcep_atm_pm3_bp2_1_5
PS3 Not assessed Available functional publications reviewed in curated sources describe ATM loss-of-function biology or assays of other ATM alterations, but no direct assay of this specific variant was identified showing failure to rescue ATM-specific function and radiosensitivity as required by the ATM framework. Therefore PS3 is not assigned.
oncokb PMID:27413114 PMID:30348496 PMID:30553448 PMID:25614872
BS3 Not assessed No direct assay of this specific variant was identified showing rescue of ATM-specific function or radiosensitivity. Therefore BS3 is not assigned.
oncokb PMID:27413114 PMID:30348496 PMID:30553448 PMID:25614872
PP1 Not assessed No segregation data were identified for this variant in affected relatives, so PP1 cannot be assigned.
PP3 N/A SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the ATM PP3 splice threshold of ≥0.2. However, ATM PP3 is specified for missense, silent/in-frame, and noncanonical intronic variants with predicted splice impact, not for an exonic frameshift variant such as this one, so PP3 is not applied.
cspec spliceai
BP4 N/A SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the ATM BP4 splice threshold of ≤0.1. However, ATM BP4 is specified for missense or splicing-prediction contexts rather than for an exonic frameshift variant, so BP4 is not applied.
cspec spliceai
PS1 N/A This variant is a frameshift deletion and does not meet the ATM PS1 framework, which is specified for missense substitutions or defined splicing comparators.
cspec vcep_atm_ps1_1_5
PM4 N/A ATM PM4 is specified for stop-loss variants. This variant is a frameshift deletion, so PM4 is not applicable.
cspec
PM1 N/A ATM PM1 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
PP2 N/A ATM PP2 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
PP4 N/A ATM PP4 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
PP5 N/A PP5 is designated not applicable in the ATM gene-specific framework and is not used.
cspec
PS2 N/A ATM PS2 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
PM6 N/A ATM PM6 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
BP1 N/A ATM BP1 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
BP3 N/A ATM BP3 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
BP5 N/A ATM BP5 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
BP6 N/A ATM BP6 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
BP7 N/A ATM BP7 is specified for synonymous or deep intronic variants and related RNA evidence. This exonic frameshift variant does not fit that rule, so BP7 is not applicable.
cspec
BS2 N/A ATM BS2 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
BS4 N/A ATM BS4 is designated not applicable in the gene-specific framework, so it is not used for this variant.
cspec
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