LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-09
Case ID: NM_000051.4_c.8287C_T_20261109_194731
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.8287C>T

ATM  · NP_000042.3:p.(Arg2763Ter)  · NM_000051.4
GRCh37: chr11:108213967 C>T  ·  GRCh38: chr11:108343240 C>T
Gene: ATM Transcript: NM_000051.4
Final call
Pathogenic
PVS1 very strong PS3 supporting PM2 supporting PM3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Arg2763Ter)
gnomAD AF
2.4786833234186e-06 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PVS1 very strong is supported by an NMD-prone ATM nonsense variant at p.Arg2763Ter.
2
Pathogenic: PS3 supporting is supported by direct prime-editing data classifying c.8287C>T as non-functional with high confidence.
3
Pathogenic: PM2 supporting is supported by a highest gnomAD v4.1 subpopulation frequency of 0.000339%.
4
Pathogenic: PM3 moderate is supported by a confident A-T proband with a second truncating ATM variant in phase-unknown configuration.
Final determination: ATM VCEP Version 1.6 Rule4 classifies the variant as Pathogenic when one very strong pathogenic criterion and at least two supporting pathogenic criteria are satisfied; PVS1 very strong, PS3 supporting, and PM2 supporting meet this rule.
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 Met at very strong: the exon-57 nonsense p.Arg2763Ter falls within the VCEP's NMD-predicted p.Ser2_Glu2979 interval.
cspec vcep_atm_pvs1_1_6 pvs1_variant_assessment PMID:17910737
PS1 N/A Not applicable: c.8287C>T produces p.Arg2763Ter, whereas ATM PS1 covers missense changes or splice variants, not nonsense variants.
cspec vcep_atm_ps1_1_6 pvs1_variant_assessment
PS2 N/A Not applicable: the ATM VCEP prohibits PS2 because informative de novo occurrences have not yet been observed for AD or AR disease.
cspec
PS3 Met Met, Supporting: direct prime-editing Table S1 measurement classified c.8287C>T as Non-functional with High confidence and DeepATM_predicted=No.
cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951
PS4 Not assessed Not assessed: patient reports document c.8287C>T in A-T cases but provide no control counts or p-value needed for the VCEP's PS4 threshold.
cspec PMID:17910737 PMID:18431795
PM1 N/A Not applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined.
cspec
PM2 Met Met at supporting: the highest gnomAD v4.1 subpopulation AF is 0.000339%, below the VCEP's <=0.001% PM2 threshold.
cspec gnomad_v4
PM3 Met Met at Moderate: one confident A-T proband with a phase-unknown second truncating ATM variant contributes 2.0 PM3 points, meeting the VCEP Moderate threshold.
vcep_atm_pm3_bp2_1_6 cspec PMID:17910737 PMID:18431795
PM4 N/A Not applicable: PM4 is limited to stop-loss variants, whereas c.8287C>T is a nonsense stop-gain producing p.Arg2763Ter.
cspec pvs1_variant_assessment
PM5 Not assessed Not assessed: p.Arg2763Ter is upstream of p.Leu3048, but PM5 requires PVS1 Very Strong and that prerequisite was not established here.
cspec pvs1_variant_assessment
PM6 N/A Not applicable: the ATM VCEP prohibits PM6 because informative de novo occurrences have not yet been observed for AD or AR disease.
cspec
PP1 Not assessed Not assessed: the variant was reported in one affected proband, but no affected relative or familial segregation count is reported to meet the VCEP PP1 thresholds.
cspec PMID:17910737 PMID:18431795
PP2 N/A Not applicable: the ATM VCEP says not to use PP2 because ATM lacks a defined low rate of benign missense variation.
cspec
PP3 N/A Not applicable: PP3's VCEP splicing path covers silent, missense/in-frame, and specified intronic variants, not this nonsense variant; SpliceAI max delta was 0.149.
cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4 N/A Not applicable: the ATM VCEP excludes PP4 for both hereditary breast cancer and ataxia telangiectasia interpretations.
cspec
PP5 N/A Not applicable: the ATM VCEP prohibits PP5 regardless of the variant's pathogenic classifications in reputable sources.
cspec
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.000079%, below the VCEP's >0.5% BA1 threshold.
cspec gnomad_v4
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 0.000079%, below the VCEP's >0.05% BS1 threshold.
cspec gnomad_v4
BS2 N/A Not applicable: the ATM VCEP v1.6 explicitly designates BS2 as not applicable.
cspec
BS3 Not assessed Not assessed: Table S1 directly measured c.8287C>T as Non-functional, while no variant-specific benign rescue result is available for BS3.
cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951
BS4 N/A Not applicable: the ATM VCEP assigns no weight to informative lack-of-segregation instances in ataxia-telangiectasia families because they are too rare.
cspec
BP1 N/A Not applicable: BP1 is prohibited for ATM because missense pathogenic variants are known, and this variant is nonsense.
cspec
BP2 Not assessed Not assessed: no unaffected adult observation or cis observation is available for c.8287C>T under the ATM VCEP BP2 framework.
vcep_atm_pm3_bp2_1_6 cspec PMID:17910737 PMID:18431795
BP3 N/A Not applicable: the ATM VCEP explicitly designates BP3 as Not Applicable for this framework.
cspec pvs1_variant_assessment
BP4 N/A Not applicable: BP4 cannot negate this nonsense variant's truncating effect; SpliceAI max delta 0.149 also exceeds the VCEP's <=0.1 no-impact cutoff.
cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5 N/A Not applicable: the ATM VCEP prohibits BP5 because additional pathogenic variants do not provide usable alternate-molecular-basis evidence in this framework.
cspec
BP6 N/A Not applicable: the ATM VCEP prohibits BP6 regardless of any benign classification reported by a reputable source.
cspec
BP7 N/A Not applicable: BP7 is restricted to synonymous or qualifying deep intronic variants, whereas c.8287C>T is a nonsense substitution.
cspec
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