LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-21
Case ID: NM_000051.4_c.7630-2A_C_20261021_125907
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.7630-2A>C

ATM  · NP_000042.3:p.?  · NM_000051.4
GRCh37: chr11:108202604 A>C  ·  GRCh38: chr11:108331877 A>C
Gene: ATM Transcript: NM_000051.4
Final call
Likely Pathogenic
PVS1 strong 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.?
gnomAD AF
1.0538387626693116e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 strong: documented aberrant splicing includes a frameshifting transcript, with the VCEP's in-frame exon-loss limit applied.
2
PM3 moderate: one confident-phenotype ataxia-telangiectasia proband was homozygous for the variant, meeting 2.0 VCEP PM3 points.
Final determination: ATM VCEP v1.6 Rule11 is satisfied by one strong pathogenic criterion and one moderate pathogenic criterion, which maps to Likely 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 Met, strong: canonical splice disruption produces exon skipping and a documented frameshift, while the in-frame exon-loss component triggers the VCEP's HEAT-domain strong limit.
cspec vcep_atm_pvs1_1_6 pvs1_variant_assessment PMID:9887333 PMID:21833744
PS1 Not assessed Not assessed: abnormal splicing is documented, but no distinct VCEP PS1 reference variant with a matched splice event and comparable prediction is available.
cspec vcep_atm_ps1_1_6 PMID:9887333 PMID:21833744
PS2 N/A Not applicable: the ATM VCEP excludes PS2 for autosomal-recessive disease because informative de novo occurrences have not been observed.
cspec PMID:25374739
PS3 Not assessed Not assessed: Table S1 reports Classification=NA, Confidence=NA, and DeepATM_predicted=NA, while available variant-specific evidence is RNA splice disruption rather than PS3-qualified rescue testing.
cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:9887333 PMID:21833744
PS4 Not assessed Not assessed: no case-control p-value or odds ratio, relative risk, hazard ratio, or lower 95% confidence interval is reported for this variant.
cspec PMID:9887333 PMID:21833744 PMID:25374739
PM1 N/A Not applicable: the ATM v1.6 CSPEC explicitly marks PM1 as Not Applicable, and no extracted ATM domain table is provided.
cspec
PM2 Not met Not met: the highest gnomAD v4.1 subpopulation AF is 0.00144145%, above the VCEP PM2 threshold of <=0.001%, with 17 observed alleles.
cspec gnomad_v4
PM3 Met Met at Moderate: one confident A-T homozygous proband contributes 2.0 PM3 points under the ATM VCEP table.
cspec vcep_atm_pm3_bp2_1_6 PMID:9887333 PMID:25374739 PMID:21833744
PM4 N/A Not applicable: the VCEP limits PM4 to stop-loss variants, while this variant is a canonical splice-site change with protein consequence p.?.
cspec
PM5 Not assessed Not assessed: an observed frameshift is reported, but the VCEP requires PVS1(RNA) Very Strong with high-quality RNA data, which is not established here.
cspec PMID:9887333 PMID:21833744
PM6 N/A Not applicable: the ATM VCEP excludes PM6 for autosomal-recessive disease because informative de novo occurrences have not been observed.
cspec PMID:25374739
PP1 Not assessed Not assessed: no informative affected-relative segregation series confirms both proband ATM variants in affected relatives, so the VCEP PP1 requirement cannot be evaluated.
cspec PMID:25374739 PMID:9887333 PMID:21833744 PMID:30067863
PP2 N/A Not applicable: the ATM v1.6 CSPEC explicitly marks PP2 as Not Applicable.
cspec
PP3 N/A Not applicable: c.7630-2A>C is the canonical acceptor -2 site, outside the VCEP PP3 splice rule despite SpliceAI max delta 0.907.
cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4 N/A Not applicable: the VCEP excludes PP4 for ATM cancer predisposition and directs ataxia-telangiectasia phenotype evidence into PM3/BP2 instead.
cspec
PP5 N/A Not applicable: the VCEP explicitly states that PP5 is not for use.
cspec
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 8.78e-06 (0.000878%), below the VCEP BA1 threshold of >0.5%.
cspec gnomad_v4
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 8.78e-06 (0.000878%), below the VCEP BS1 threshold of >0.05%.
cspec gnomad_v4
BS2 N/A Not applicable: the ATM VCEP explicitly marks BS2 Not Applicable, despite zero homozygotes in gnomAD v4.1.
cspec gnomad_v4
BS3 Not assessed Not assessed: Table S1 reports Classification=NA, Confidence=NA, and DeepATM_predicted=NA, and no variant-specific benign rescue assay is available for BS3.
cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:9887333 PMID:21833744
BS4 N/A Not applicable: the ATM VCEP states that informative lack of cosegregation in ataxia-telangiectasia families is too rare to receive weight.
cspec
BP1 N/A Not applicable: the ATM v1.6 CSPEC explicitly marks BP1 as Not Applicable.
cspec
BP2 Not assessed Not assessed: no unaffected adult or qualifying cis observation is documented for the BP2 requirement.
cspec vcep_atm_pm3_bp2_1_6
BP3 N/A Not applicable: the ATM VCEP explicitly marks BP3 as not applicable, and this variant is a documented canonical splice-site change.
cspec
BP4 Not met Not met: SpliceAI max delta 0.907 exceeds the VCEP BP4 no-predicted-impact cutoff of <=0.1.
cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5 N/A Not applicable: the VCEP instructs that BP5 should not be used for ATM because multiple pathogenic variants may coexist without a noticeable phenotype difference.
cspec
BP6 N/A Not applicable: the VCEP explicitly states that BP6 is not for use.
cspec
BP7 N/A Not applicable: c.7630-2A>C is a canonical acceptor -2 splice-site substitution, not synonymous or deep intronic beyond -21.
cspec PMID:9887333 PMID:21833744
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