Variant classification summary

NM_000051.4:c.3077+1G>A

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108142134 G>A · GRCh38: chr11:108271407 G>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PS3 supporting PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

6.196040234606868e-07 (v4.1)

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PVS1 very strong is assigned by the ATM VCEP's exact list-A entry for c.3077+1G>A with disrupted reading frame and predicted NMD.

2

Pathogenic: PS3 supporting is met by direct prime-editing data classifying c.3077+1G>A as non-functional with high confidence.

3

Pathogenic: PM2 supporting is met because the highest gnomAD subpopulation frequency is below the ATM VCEP's 0.001% threshold.

Final determination: ATM VCEP Version 1.6 Rule4 is satisfied by one very strong pathogenic criterion and at least two supporting pathogenic criteria, resulting in 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, very strong: the ATM VCEP pre-assigned list-A row for c.3077+1G>A specifies disrupted reading frame, predicted NMD, and full-strength PVS1.	vcep_atm_pvs1_1_6 cspec pvs1_variant_assessment
PS1	Not assessed	Not assessed: the variant has a PVS1 baseline, but the PS1 splicing table has no matching reference-variant entry for c.3077+1G>A or p.?.	cspec vcep_atm_ps1_1_6 vcep_atm_pvs1_1_6
PS2	N/A	Not applicable: the ATM VCEP explicitly marks PS2 as not applicable.	cspec
PS3	Met	Met at Supporting: direct prime-editing data classified c.3077+1G>A as Non-functional with High confidence and DeepATM_predicted=No.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: the available study reported gene-level ATM OR 1.88 (95% CI 1.10–3.22, P=.02), not variant-specific case-control evidence for c.3077+1G>A.	PMID:32853339
PM1	N/A	Not applicable: the ATM VCEP excludes PM1 because benign and pathogenic variants occur in the same domains and hotspots are not well defined.	cspec
PM2	Met	Met at supporting: the highest gnomAD subpopulation frequency is 0.00008474834825469252%, below the VCEP's ≤0.001% PM2 threshold.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no affected A-T proband, phase, or pathogenic variant-in-trans observation is available to assign the VCEP's PM3 points.	cspec vcep_atm_pm3_bp2_1_6
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants, whereas c.3077+1G>A is a canonical splice-site substitution producing p.?.	cspec
PM5	N/A	Not applicable: this is a predicted splice variant without RNA data, which the ATM PM5 rule expressly excludes.	cspec vcep_atm_pvs1_1_6
PM6	N/A	Not applicable: the ATM VCEP explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no documented affected relatives or segregation results are available to meet the VCEP's 1-, 2-, or 3-relative thresholds.	cspec
PP2	N/A	Not applicable: the ATM VCEP states that ATM lacks a defined low rate of benign missense variation.	cspec
PP3	N/A	Not applicable: the VCEP's PP3 splicing path excludes donor and acceptor 1,2 sites, and this variant is the canonical donor +1.	cspec spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the VCEP excludes PP4 for ATM-related breast cancer and incorporates autosomal-recessive phenotype evidence into the PM3/BP2 table.	cspec
PP5	N/A	Not applicable: the ATM VCEP prohibits PP5, regardless of reputable-source classifications reporting this variant as pathogenic.	cspec
BA1	Not met	Not met: the highest observed gnomAD subpopulation frequency is 8.474834825469252e-07, far below the >0.5% BA1 threshold.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest observed gnomAD subpopulation frequency is 8.474834825469252e-07, below the >0.05% BS1 threshold.	cspec gnomad_v4 gnomad_v2
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Not met	Not met: direct prime-editing classified the variant as Non-functional, providing impairment evidence rather than rescue of an ATM-specific feature or radiosensitivity.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	Not applicable: the ATM VCEP explicitly marks BS4 as not applicable.	cspec
BP1	N/A	Not applicable: the ATM VCEP states that pathogenic missense variants are known for ATM.	cspec
BP2	N/A	Not applicable: canonical c.3077+1G>A has SpliceAI maximum delta 0.992, conflicting with the VCEP requirement that BP2 variants lack predicted clinically important splicing effects.	cspec vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 Not Applicable, and this variant is a canonical splice-site substitution rather than an in-frame repeat-region deletion.	cspec
BP4	Not met	Not met: SpliceAI max delta 0.992 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 VCEP prohibits BP5 because ATM's low penetrance permits pathogenic variants to co-occur without a noticeable phenotype difference.	cspec
BP6	N/A	Not applicable: the ATM VCEP prohibits BP6, regardless of reputable-source classifications reporting this variant as benign.	cspec
BP7	Not assessed	Not assessed: BP7(RNA) requires observed absence of an aberrant RNA defect, and no qualifying RNA result is available for this canonical donor +1 variant.	cspec

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