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

VUS

PVS1 very strong PM3 very strong

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 very strong: the canonical splice-site variant causes aberrant ATM splicing and absent ATM protein.

2

PM3 very strong: 10.0 aggregated affected A-T observations exceed the ATM VCEP threshold of 8 points.

Final determination: Under the ATM VCEP Version 1.6 criteria-combination framework, PVS1 very strong plus PM3 very strong does not satisfy a listed pathogenic or benign rule without an additional qualifying criterion, so the result is VUS.

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, very strong: canonical -2 splice-site disruption caused aberrant transcripts and absent ATM protein, with no applicable VCEP downgrade rule.	cspec vcep_atm_pvs1_1_6 pvs1_variant_assessment PMID:10330348 PMID:9887333
PS1	Not assessed	Not assessed: observed exon-54 splicing defects are documented, but no separate known pathogenic reference variant with the same event is identified in the governing PS1 table.	cspec vcep_atm_ps1_1_6 PMID:10330348 PMID:9887333
PS2	N/A	Not applicable: the ATM VCEP Version 1.6 marks PS2 as Not Applicable.	cspec
PS3	Not assessed	Not assessed: the Sun Table S1 row has Confidence=NA and DeepATM_predicted=NA, while the VCEP routes observed RNA splice defects to PVS1_Strength(RNA), not PS3.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:10330348 PMID:9887333
PS4	Not assessed	Not assessed: reported cases are available, but no qualifying case-control p-value and odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is reported.	cspec PMID:9887333 PMID:10330348 PMID:25374739 PMID:30067863
PM1	N/A	Not applicable: the ATM VCEP explicitly marks PM1 as Not Applicable and provides no ATM domain-table entry for this assessment.	cspec
PM2	Not met	Not met: the highest gnomAD subpopulation AF is 0.001441% (17 alleles), exceeding the VCEP's <=0.001% PM2 threshold and not qualifying for the n=1 exception.	cspec gnomad_v2 gnomad_v4
PM3	Met	Met, 10.0 aggregated PM3 points from one confirmed-in-trans A-T case plus additional affected-family observations exceeds the VCEP Very Strong threshold of 8 points.	cspec vcep_atm_pm3_bp2_1_6 PMID:25374739 PMID:9887333 PMID:10330348
PM4	N/A	Not applicable: the VCEP limits PM4 to stop-loss variants, whereas this is a canonical splice-site variant with p.? consequence.	cspec pvs1_variant_assessment
PM5	Not assessed	Not assessed: RNA confirms aberrant splicing, but the required VCEP PVS1(RNA) Very Strong assignment and NMD-prone truncating eligibility are not established.	cspec vcep_atm_pvs1_1_6 PMID:9887333
PM6	N/A	Not applicable: the ATM VCEP Version 1.6 marks PM6 as Not Applicable.	cspec
PP1	Not assessed	Not assessed: one affected child had paternal c.7630-2A>C, but no affected relative was documented for the VCEP's one-relative segregation threshold.	cspec PMID:25374739 PMID:9887333
PP2	N/A	Not applicable: the ATM VCEP explicitly marks PP2 as Not Applicable for this VCEP framework.	cspec
PP3	N/A	Not applicable: the VCEP PP3 splice rule excludes intronic variants at donor and acceptor 1,2 sites, and c.7630-2A>C is an acceptor -2 variant.	cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the ATM VCEP excludes PP4 for hereditary breast cancer and as separate evidence for autosomal recessive ataxia-telangiectasia.	cspec
PP5	N/A	Not applicable: the ATM VCEP explicitly prohibits PP5, regardless of available pathogenic assertions from reputable sources.	cspec
BA1	Not met	Not met: gnomAD grpmax filtering AF is 8.78e-06 (0.000878%), below the VCEP's >0.5% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD grpmax filtering AF is 8.78e-06 (0.000878%), below the VCEP's >0.05% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Not assessed	Not assessed: no qualifying benign rescue result exists, and the exact Table S1 row is Pathogenic with Confidence=NA and DeepATM_predicted=NA.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 PMID:10330348 PMID:9887333
BS4	N/A	Not applicable: the ATM VCEP Version 1.6 marks BS4 as Not Applicable.	cspec
BP1	N/A	Not applicable: the ATM VCEP explicitly marks BP1 as Not Applicable in its criterion specifications.	cspec
BP2	Not assessed	Not assessed: no qualifying unaffected adult observation with documented pathogenic-variant trans or cis phase is available for the VCEP BP2 table.	cspec vcep_atm_pm3_bp2_1_6 PMID:25374739 PMID:9887333 PMID:10330348 PMID:30067863
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as not applicable for this framework.	cspec
BP4	Not met	Not met: SpliceAI maximum delta 0.907 exceeds the VCEP BP4 no-impact threshold of ≤0.1.	cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the ATM VCEP explicitly instructs users not to apply BP5 because of observed multiple pathogenic variants and ATM's low penetrance.	cspec
BP6	N/A	Not applicable: the ATM VCEP explicitly prohibits BP6, regardless of available benign assertions from reputable sources.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or deep intronic variants beyond acceptor -21, whereas c.7630-2A>C is an acceptor -2 splice-site variant.	cspec

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