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

Likely Pathogenic

PVS1 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

Likely Pathogenic: PVS1 strong reflects a canonical +1 splice disruption with an in-frame exon-20 skip and an intact protein remainder.

2

Likely Pathogenic: PS3 supporting reflects a high-confidence direct prime-editing result showing the exact variant is non-functional.

3

Likely Pathogenic: PM2 supporting reflects a gnomAD maximum subpopulation frequency below the ATM VCEP rarity threshold.

Final determination: ATM VCEP Rule12 classifies the variant as Likely Pathogenic when one Pathogenic.Strong criterion and at least two Pathogenic.Supporting criteria are met.

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 +1 splice disruption predicts an in-frame 156-nucleotide exon-20 skip, triggering the VCEP's intact-remainder/escape-from-NMD downgrade rule.	cspec vcep_atm_pvs1_1_6 pvs1_variant_assessment vcep_suppl_tables1_pmid_40580951 PMID:40580951
PS1	Not assessed	Not assessed: the governing ATM PS1 splicing table contains no c.3077+1G>A or p.? entry establishing a matching reference splice event.	cspec vcep_atm_ps1_1_6
PS2	N/A	Not applicable: the ATM VCEP specification explicitly marks PS2 as not applicable.	cspec
PS3	Met	Met at Supporting: direct prime-editing row classifies 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 only case-control result was gene-level ATM data (OR=1.88, lower 95% CI=1.10), not an exact-variant estimate.	cspec PMID:32853339
PM1	N/A	Not applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and hotspots are not well defined.	cspec
PM2	Met	Met at Supporting: highest observed gnomAD subpopulation AF is 0.0000847%, below the VCEP PM2 threshold of <=0.001%.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no qualifying affected-proband observation or phase-established pathogenic ATM variant in trans is available for PM3 point assignment.	vcep_atm_pm3_bp2_1_6 cspec
PM4	N/A	Not applicable: PM4 is restricted to stop-loss variants, whereas c.3077+1G>A is a canonical splice-site variant with p.? consequence.	cspec
PM5	N/A	Not applicable: PM5 requires an observed NMD-prone truncating splice variant with PVS1(RNA) Very Strong and high-quality RNA data, none of which is available.	cspec
PM6	N/A	Not applicable: the ATM VCEP specification explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no documented affected-relative segregation count or variant-specific parental testing is available to meet the PP1 thresholds.	cspec
PP2	N/A	Not applicable: the ATM VCEP states that ATM does not have a defined low rate of benign missense variation.	cspec
PP3	N/A	Not applicable: the VCEP PP3 splicing path excludes canonical donor/acceptor ±1,2 variants, including c.3077+1G>A.	cspec spliceai
PP4	N/A	Not applicable: the ATM VCEP excludes PP4 for hereditary breast cancer and incorporates ataxia-telangiectasia phenotype evidence into PM3/BP2.	cspec
PP5	N/A	Not applicable: the ATM VCEP explicitly prohibits PP5, regardless of the available ClinVar pathogenic or likely pathogenic submissions.	cspec clinvar
BA1	Not met	Not met: highest observed gnomAD subpopulation AF is 8.47e-7, far below the VCEP BA1 threshold of >0.5%.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest observed gnomAD subpopulation AF is 0.0000847%, below the VCEP BS1 threshold of >0.05%.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Not met	Not met: direct prime-editing measurement classifies c.3077+1G>A as Non-functional, not as rescuing 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 specification explicitly marks BS4 as not applicable.	cspec
BP1	N/A	Not applicable: the ATM VCEP states that missense pathogenic variants are known for ATM, and this variant is canonical splice, not missense.	cspec
BP2	Not assessed	Not assessed: no qualifying unaffected-adult observation documents this variant in trans or cis with a pathogenic ATM variant for BP2.	vcep_atm_pm3_bp2_1_6 cspec
BP3	N/A	Not applicable: the ATM VCEP explicitly marks BP3 as Not Applicable, and this variant is canonical splice-site rather than a repeat-region in-frame indel.	cspec
BP4	Not met	Not met: SpliceAI max delta 0.992 exceeds the VCEP BP4 no-impact threshold of ≤0.1.	cspec spliceai
BP5	N/A	Not applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants may occur without a noticeable phenotype difference and ATM has low penetrance.	cspec
BP6	N/A	Not applicable: the ATM VCEP explicitly prohibits BP6, so reputable-source benign reports cannot establish this criterion.	cspec
BP7	N/A	Not applicable: BP7 covers synonymous or deep intronic variants beyond donor +7 or acceptor −21, not canonical donor +1 variants.	cspec

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