Variant classification summary

NM_000051.4:c.1065+1G>C

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108117855 G>C · GRCh38: chr11:108247128 G>C

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

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the VCEP exact-row assignment predicts a reading-frame-disrupting, NMD-prone splice consequence.

2

PS3 supporting: direct prime-editing testing classified c.1065+1G>C as non-functional with high confidence.

3

PM2 supporting: c.1065+1G>C is absent from gnomAD v2.1 and v4.1.

Final determination: ATM VCEP Version 1.6 Rule4 classifies a variant as Pathogenic when one very strong pathogenic criterion and at least two supporting pathogenic criteria are satisfied; here these are PVS1, PS3, and PM2.

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 ATM VCEP exact-row assignment for c.1065+1G>C states disrupted reading frame and predicted NMD in N-terminal HEAT repeats.	vcep_atm_pvs1_1_6 pvs1_variant_assessment cspec
PS1	Not assessed	Not assessed: the ATM PS1 splicing table contains no c.1065+1G>C or p.? comparator entry, so no pre-assigned PS1 code can be applied.	cspec vcep_atm_ps1_1_6 spliceai
PS2	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks PS2 as not applicable.	cspec
PS3	Met	Met at Supporting: direct prime-editing testing classified c.1065+1G>C 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: gene-level ATM pathogenic variants showed OR=2.1 and p=0.031, but the study did not identify NM_000051.4:c.1065+1G>C specifically.	cspec PMID:30287823
PM1	N/A	Not applicable: the ATM VCEP explicitly marks PM1 Not Applicable, and no authoritative ATM domain-table entry is present.	cspec
PM2	Met	Met at Supporting: the highest observed gnomAD subpopulation frequency is 0% because the variant is absent from both gnomAD v2.1 and v4.1, below the <=0.001% threshold.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, phase, or pathogenic-in-trans evidence was available, and ATM_PM3_BP2_1.6.pdf contains no entry for c.1065+1G>C or p.?.	cspec vcep_atm_pm3_bp2_1_6
PM4	Not met	Not met: PM4 is restricted to stop-loss variants, whereas c.1065+1G>C is a canonical splice-donor variant producing a predicted frameshift and p.?.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: PM5 requires observed splice impact with high-quality RNA and PVS1(RNA) Very Strong, whereas this variant has predicted splice impact without RNA data.	cspec
PM6	N/A	Not applicable: the ATM VCEP v1.6 explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation data are documented to evaluate the VCEP's autosomal-recessive PP1 thresholds.	cspec
PP2	N/A	Not applicable: the ATM VCEP explicitly marks PP2 Not Applicable for this interpretation.	cspec
PP3	N/A	Not applicable: c.1065+1G>C is a canonical donor +1 variant, outside the VCEP PP3 splicing scope for variants beyond donor/acceptor 1,2 sites.	cspec spliceai
PP4	N/A	Not applicable: the VCEP excludes PP4 for hereditary breast cancer and does not allow it separately for autosomal-recessive ataxia telangiectasia.	cspec
PP5	N/A	Not applicable: the VCEP prohibits PP5, regardless of the available ClinVar likely-pathogenic submission.	cspec
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its group-maximum allele frequency does not exceed the VCEP's >0.5% BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so its group-maximum allele frequency does not exceed the VCEP's >0.05% BS1 threshold.	cspec gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the VCEP states that BS2 should not be used because ATM has incomplete penetrance.	cspec
BS3	Not met	Not met: direct prime-editing testing classified c.1065+1G>C as Non-functional, not Functional, with High confidence.	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 v1.6 explicitly marks BS4 as not applicable.	cspec
BP1	N/A	Not applicable: the ATM VCEP explicitly marks BP1 Not Applicable for this interpretation.	cspec
BP2	Not assessed	Not assessed: no cis/trans pathogenic-partner observation or unaffected-adult BP2 data was available, and ATM_PM3_BP2_1.6.pdf contains no entry for c.1065+1G>C or p.?.	cspec vcep_atm_pm3_bp2_1_6
BP3	N/A	Not applicable: the ATM VCEP says not to use BP3, and this variant is a splice-donor substitution rather than an in-frame repeat-region indel.	cspec pvs1_variant_assessment
BP4	Not met	Not met: SpliceAI maximum delta score is 0.973, exceeding the VCEP BP4 no-impact threshold of <=0.1.	cspec spliceai
BP5	N/A	Not applicable: the VCEP prohibits BP5 because multiple pathogenic variants can coexist without a noticeable phenotype difference in low-penetrance ATM disease.	cspec
BP6	N/A	Not applicable: the VCEP prohibits BP6, so no reputable-source benign assertion can establish this criterion.	cspec
BP7	N/A	Not applicable: c.1065+1G>C is a canonical donor +1 variant, not a synonymous or deep intronic variant beyond the VCEP BP7 boundaries.	cspec

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