LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-04-12
Case ID: NM_000051.4_c.8395_8404del_20260412_192214
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.8395_8404del

ATM  · NP_000042.3:p.(Phe2799LysfsTer4)  · NM_000051.4
GRCh37: chr11:108214064 ATTTCAGTGCC>A  ·  GRCh38: chr11:108343337 ATTTCAGTGCC>A
Gene: ATM Transcript: NM_000051.4
Final call
Likely Pathogenic
PVS1_VeryStrong 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.(Phe2799LysfsTer4)
gnomAD AF
ClinVar
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
ATM HBOP VCEP v1.5 supports PVS1 for null variants through the ATM PVS1 decision tree, and this variant is an exonic frameshift with predicted consequence p.(Phe2799LysfsTer4)/p.(F2799Kfs*4).
2
ATM-specific PM5_Supporting applies to truncating variants with premature termination codons upstream of p.Arg3047; this variant truncates at codon 2802, upstream of that boundary.
3
PM2 was not applied because gnomAD v4 shows 20/1613922 alleles (0.00124%), slightly above the ATM PM2_Supporting threshold of 0.001%.
4
ClinVar contains a concordant ClinGen HBOP expert-panel Pathogenic classification for this variant, but that assertion was treated as contextual support rather than as a standalone ACMG criterion.
Final determination:
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 ATM HBOP VCEP v1.5 allows PVS1 via the ATM decision tree for null variants. NM_000051.4:c.8395_8404del is an exonic frameshift with predicted protein consequence p.(Phe2799LysfsTer4)/p.(F2799Kfs*4); the event is upstream of the ATM truncation boundary referenced in the specification and there is no evidence from SpliceAI of an alternate splice mechanism that would replace the expected loss-of-function interpretation.
cspec vcep_a_t_m___p_v_s_1___1___5 spliceai
PS1 Not assessed No same-amino-acid or same-splicing-event reference variant evidence was extracted in the workspace for PS1 assessment.
cspec vcep_a_t_m___p_s_1___1___5
PS2 N/A ATM HBOP VCEP states PS2 is not used for ATM.
cspec
PS3 Not assessed The workspace contains ATM functional-framework materials, but no curated variant-specific rescue/failure-to-rescue data for c.8395_8404del were extracted for direct PS3 use.
cspec PMID:19147735 PMID:21665257 PMID:21833744 PMID:27413114 PMID:30348496 PMID:30553448
PS4 Not assessed The workspace did not provide a case-control analysis satisfying the ATM PS4 rule. Existing literature citations and ClinVar submissions indicate prior observations, but the needed odds ratio/risk estimate was not extracted for independent PS4 assignment.
cspec clinvar PMID:10817650 PMID:12815592 PMID:19147735 PMID:21665257 PMID:21833744
PM1 N/A ATM HBOP VCEP states PM1 should not be used because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined.
cspec
PM2 Not met ATM PM2 is downgraded to PM2_Supporting and requires frequency <=0.001% in gnomAD v4. This variant is present at 20/1613922 alleles (0.00124%), so the ATM threshold is not met.
cspec gnomad_v4
PM3 Not assessed ATM PM3 requires proband-level recessive evidence with phase/zygosity scoring. The workspace did not extract proband-specific in-trans or homozygous observations for this variant.
cspec vcep_a_t_m___p_m_3___b_p_2___1___5
PM4 N/A ATM PM4 is reserved for stop-loss variants and not for this frameshift deletion.
cspec
PM5 Met ATM HBOP VCEP specifies PM5_Supporting for frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a stop at codon 2802, which is upstream of p.Arg3047.
cspec
PM6 N/A ATM HBOP VCEP states PM6 is not used for ATM.
cspec
PP1 Not assessed No family segregation data were extracted for affected relatives with biallelic ATM variants, so PP1 was not applied.
cspec PMID:12815592
PP2 N/A ATM HBOP VCEP states PP2 should not be used because ATM does not have a defined low rate of benign missense variation.
cspec
PP3 Not assessed PP3 is not applied. The variant is not a missense change, SpliceAI does not predict splice impact (max delta 0.07), and the ATM specification notes splice-prediction PP3 should not be added on top of PVS1-based loss-of-function interpretation.
cspec spliceai
PP4 N/A ATM HBOP VCEP states PP4 should not be used for ATM in either the dominant cancer setting or as a separate line for A-T because phenotype evidence is already built into the PM3/BP2 framework.
cspec
PP5 N/A PP5 is not used by this VCEP.
cspec
BA1 Not met The gnomAD v4 frequency is far below the ATM BA1 stand-alone threshold (>0.5%).
cspec gnomad_v4
BS1 Not met The gnomAD v4 frequency is far below the ATM BS1 threshold (>0.05%).
cspec gnomad_v4
BS2 N/A ATM HBOP VCEP states BS2 should not be used because ATM has incomplete penetrance.
cspec
BS3 Not assessed No variant-specific evidence showing rescue of ATM-specific function or radiosensitivity was extracted for this allele, so BS3 was not applied.
cspec PMID:19147735 PMID:21665257 PMID:21833744 PMID:27413114 PMID:30348496 PMID:30553448
BS4 N/A ATM HBOP VCEP states BS4 should not be used.
cspec
BP1 N/A ATM HBOP VCEP states BP1 should not be used.
cspec
BP2 Not assessed ATM BP2 also requires proband-level co-occurrence/phase information in unaffected individuals; no such evidence was extracted in the workspace.
cspec vcep_a_t_m___p_m_3___b_p_2___1___5
BP3 N/A ATM HBOP VCEP states BP3 should not be used.
cspec
BP4 Not assessed SpliceAI shows no significant splice impact (max delta 0.07), but BP4 is not used here because the variant is an obvious frameshift loss-of-function allele and splice-only benign computational evidence does not address the primary predicted protein-damaging mechanism.
cspec spliceai
BP5 N/A ATM HBOP VCEP states BP5 should not be used.
cspec
BP6 N/A BP6 is not used by this VCEP.
cspec
BP7 N/A ATM BP7 applies to synonymous or deep intronic variants, not to this exonic frameshift deletion.
cspec
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