LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-06-09
Case ID: NM_000051.4_c.5983G_T_20260609_190547
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.5983G>T

ATM  · NP_000042.3:p.(Glu1995Ter)  · NM_000051.4
GRCh37: chr11:108183202 G>T  ·  GRCh38: chr11:108312475 G>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.(Glu1995Ter)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000051.4:c.5983G>T (p.Glu1995Ter) is a nonsense variant in exon 40 of 63 of ATM, a gene where loss of function is a well-established mechanism for autosomal recessive ataxia-telangiectasia. The premature termination codon lies well upstream of the final exon and is predicted to trigger nonsense-mediated decay, removing all critical C-terminal domains (FAT, PI3K, FATC). Under the ATM VCEP v1.5 PVS1 decision tree, this meets PVS1 at Very Strong strength.
2
The variant is absent from gnomAD v4.1 and v2.1 (0 alleles observed), meeting the ATM VCEP v1.5 PM2_Supporting threshold of allele frequency ≤0.001% in the gnomAD v4 dataset.
3
As a truncating variant with a premature termination codon at p.Glu1995, located upstream of p.Arg3047, PM5_Supporting applies per ATM VCEP v1.5 specifications.
4
No experimental functional data (PS3/BS3), case-control enrichment data (PS4), de novo observations (PS5), or co-segregation data (PP1) were identified for this specific variant in the reviewed literature. None of the three publications reviewed (PMID:27413114, PMID:30348496, PMID:30553448) mentioned NM_000051.4:c.5983G>T.
5
Applying the ATM VCEP v1.5 final classification rules (Richards et al. 2015 combination framework): PVS1 (Very Strong) plus two Supporting pathogenic criteria (PM2_Supporting, PM5_Supporting) satisfies Rule 4 (1 Pathogenic Very Strong + ≥2 Pathogenic Supporting), resulting in a final classification of Pathogenic.
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 NM_000051.4:c.5983G>T is a nonsense variant (p.Glu1995Ter) in exon 40 of 63 of ATM, a gene where loss of function is a well-established disease mechanism for ataxia-telangiectasia. The premature termination codon lies well upstream of the final exon-exon junction and is predicted to trigger nonsense-mediated decay. The ATM VCEP v1.5 PVS1 decision tree was applied; the variant truncates the protein prior to the FAT domain (aa 2097–2488), PI3K domain (aa 2623–2974), and FATC domain (aa 3026–3055). The VCEP supplement (PMID:40580951, Table S1) classifies this variant as 'Non-functional' with a combined score of 0.960.
vcep_atm_pvs1_1_5 vcep_suppl_tables1_pmid_40580951 pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1 N/A PS1 per ATM VCEP v1.5 applies only to missense changes (requiring splice exclusion for both alterations) or splicing variants (using the ATM PS1 Splicing table). This variant is a nonsense change and neither the missense nor splicing comparator framework applies.
vcep_atm_ps1_1_5
PS2 N/A PS2 is not applicable per ATM VCEP v1.5 specifications.
cspec
PS3 Not assessed No experimental functional assay data were identified for NM_000051.4:c.5983G>T. The ATM VCEP Supplement Table S1 (PMID:40580951) lists this variant with a 'Non-functional' designation, but the evidence source is 'Computational prediction' (eDA), not experimental functional data. PS3 under ATM VCEP v1.5 requires experimental evidence of failure to rescue ATM-specific features (e.g., phosphorylation of ATM-specific targets) with or without radiosensitivity data. None of the three publications reviewed (PMID:27413114, PMID:30348496, PMID:30553448) mentioned this specific variant.
PS4 Not met No case-control study meeting ATM VCEP v1.5 PS4 criteria (p ≤ 0.05 AND odds ratio/hazard ratio/relative risk ≥2 OR lower 95% CI ≥1.5) was identified for this variant. The variant is present in ClinVar (Variation ID: 127398) with multiple clinical laboratories classifying it as Pathogenic for ataxia-telangiectasia, but ClinVar does not provide quantitative case enrichment data sufficient to satisfy PS4 under the VCEP framework.
clinvar
PS5 Not assessed No de novo occurrence data were identified for NM_000051.4:c.5983G>T. PS5 requires confirmation that the variant occurred de novo with both parental samples confirmed to be negative. None of the three reviewed publications addressed de novo occurrence of this variant.
PM1 N/A PM1 is not applicable per ATM VCEP v1.5 specifications.
cspec
PM2 Met NM_000051.4:c.5983G>T is absent from gnomAD v4.1 (0 alleles out of population database) and gnomAD v2.1. The allele frequency of 0.0% is well below the ATM VCEP v1.5 PM2_Supporting threshold of ≤0.001% in the gnomAD v4 dataset.
gnomad_v4 gnomad_v2
PM5 Met NM_000051.4:c.5983G>T is a nonsense variant producing a premature termination codon at p.Glu1995Ter, which is upstream of p.Arg3047. Under ATM VCEP v1.5, PM5_Supporting applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.
cspec
PM6 N/A PM6 is not applicable per ATM VCEP v1.5 specifications.
cspec
PP1 Not met No co-segregation data were identified for NM_000051.4:c.5983G>T in families with ataxia-telangiectasia. PP1 under ATM VCEP v1.5 requires segregation of the variant with disease in affected relatives (1 relative for Supporting, 2 for Moderate, ≥3 for Strong). None of the three reviewed publications contained pedigree or segregation data for this variant.
PP2 N/A PP2 is not applicable per ATM VCEP v1.5 specifications.
cspec
PP3 N/A PP3 per ATM VCEP v1.5 applies to missense variants with REVEL >0.7333 or splicing variants with SpliceAI ≥0.2. This variant is a nonsense change; REVEL score is not available and SpliceAI max delta is 0.00. Neither the missense nor splicing PP3 criteria apply to a nonsense variant.
cspec spliceai
PP4 N/A PP4 is not applicable per ATM VCEP v1.5 specifications.
cspec
PP5 N/A PP5 is not applicable per ATM VCEP v1.5 specifications.
cspec
BA1 Not met NM_000051.4:c.5983G>T is absent from gnomAD v4.1. The ATM VCEP v1.5 BA1 threshold requires a Grpmax Filtering AF >0.5% in the gnomAD v4 dataset. With an allele frequency of 0.0%, BA1 is not met.
gnomad_v4
BS1 Not met NM_000051.4:c.5983G>T is absent from gnomAD v4.1. The ATM VCEP v1.5 BS1 threshold requires a Grpmax Filtering AF >0.05% in the gnomAD v4 dataset. With an allele frequency of 0.0%, BS1 is not met.
gnomad_v4
BS2 N/A BS2 is not applicable per ATM VCEP v1.5 specifications.
cspec
BS3 Not assessed No experimental functional assay data demonstrating rescue of ATM function were identified for NM_000051.4:c.5983G>T. BS3 under ATM VCEP v1.5 requires experimental evidence that the variant rescues either an ATM-specific feature (e.g., phosphorylation of ATM-specific targets) with or without radiosensitivity. The VCEP Supplement Table S1 (PMID:40580951) is computational, not experimental. None of the three reviewed publications mentioned this specific variant.
BS4 N/A BS4 is not applicable per ATM VCEP v1.5 specifications.
cspec
BP1 N/A BP1 is not applicable per ATM VCEP v1.5 specifications.
cspec
BP2 Not assessed The ATM VCEP v1.5 BP2 point system requires observation of the variant in unaffected (non-A-T) individuals, scored by zygosity and phase relative to a pathogenic variant. No such data were identified for NM_000051.4:c.5983G>T in the reviewed literature or databases.
BP4 N/A BP4 per ATM VCEP v1.5 is defined for missense variants (REVEL ≤0.249) and splicing variants (SpliceAI ≤0.1). This variant is a nonsense change with a definitive impact on the protein product via premature termination; the SpliceAI score of 0.00 is irrelevant to the variant's primary mechanism, and applying BP4 for absent splicing impact would be inappropriate when PVS1 already addresses the null variant effect.
cspec spliceai
BP5 N/A BP5 is not applicable per ATM VCEP v1.5 specifications.
cspec
BP6 N/A BP6 is not applicable per ATM VCEP v1.5 specifications.
cspec
BP7 N/A BP7 per ATM VCEP v1.5 applies to synonymous and deep intronic variants (further than +7 at donor sites and further than -21 at acceptor sites). This variant is a nonsense change and does not meet the BP7 criteria.
cspec
BP3 N/A BP3 is not applicable per ATM VCEP v1.5 specifications (in-frame deletions/insertions in non-repeat regions).
PM3 N/A PM3 was excluded from this assessment per adjudication instructions.
PM4 N/A PM4 per ATM VCEP v1.5 is restricted to stop-loss variants. This variant is a stop-gain (nonsense), not a stop-loss.
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