Variant classification summary

NM_000051.4:c.2638+11A>G

ATM · NP_000042.3:p.? · NM_000051.4

GRCh37: chr11:108138080 A>G · GRCh38: chr11:108267353 A>G

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.?

gnomAD AF

4.340240102082447e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the gnomAD v4.1 grpmax FAF is 0.000739%, below the ATM VCEP 0.001% threshold.

2

BP4 supporting: SpliceAI maximum delta score is 0.00, meeting the ATM VCEP no-splice-impact threshold.

Final determination: ATM VCEP Version 1.5 Rule31 requires at least one Benign Supporting criterion and at least one Pathogenic Supporting criterion and maps that combination to Uncertain Significance - Conflicting Evidence.

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	Not met	Not met: the intronic +11 variant has a SpliceAI maximum delta score of 0.00, with no predicted splice defect or demonstrated loss-of-function consequence.	cspec vcep_atm_pvs1_1_5
PS1	Not assessed	Not assessed: c.2638+11A>G has protein consequence p.? and SpliceAI max delta 0.00, without an established pathogenic splice comparator showing the same event.	cspec vcep_atm_ps1_1_5 spliceai
PS2	N/A	Not applicable: the ATM VCEP version 1.5 explicitly excludes PS2 from use.	cspec
PS3	Not assessed	Not assessed: no variant-specific ATM functional assay result is documented for NM_000051.4:c.2638+11A>G.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not assessed	Not assessed: no exact-variant case-control p-value, effect estimate, or confidence interval is available to test the ATM PS4 thresholds.	cspec PMID:25394175
PM1	N/A	Not applicable: c.2638+11A>G is intronic with protein consequence p.?, so no residue can be compared against an approved ATM domain.	cspec
PM2	Met	Met at Supporting: gnomAD v4.1 grpmax FAF is 7.39e-06 (0.000739%), below the ≤0.001% PM2 threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, phase, or trans/cis observations are available to assign ATM VCEP PM3 points.	cspec vcep_atm_pm3_bp2_1_5
PM4	N/A	Not applicable: c.2638+11A>G is an intronic single-nucleotide substitution with no established protein-length change or stop-loss consequence.	cspec
PM5	Not assessed	Not assessed: the ATM splice-specific PM5 route requires observed PVS1_VS(RNA) impact, but only SpliceAI max delta 0.00 is available.	cspec vcep_atm_pvs1_1_5 spliceai
PM6	N/A	Not applicable: the ATM VCEP version 1.5 explicitly excludes PM6 from use.	cspec
PP1	Not assessed	Not assessed: no affected-relative segregation count or genotype-linked meioses are documented for this variant.	cspec
PP2	N/A	Not applicable: c.2638+11A>G is intronic and produces no defined missense consequence (p.?), whereas PP2 is restricted to missense context.	cspec
PP3	Not met	Not met: SpliceAI maximum delta score is 0.00, below the ATM VCEP PP3 splice-impact threshold of ≥0.2.	cspec spliceai
PP4	N/A	Not applicable: the ATM VCEP explicitly excludes PP4, and no phenotype for a carrier of this exact variant is reported.	cspec PMID:24418350
PP5	N/A	Not applicable: ATM VCEP excludes PP5, and ClinVar shows no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 7.39e-06 (0.000739%), below the >0.5% BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 7.39e-06 (0.000739%), below the >0.05% BS1 threshold.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance.	cspec
BS3	Not assessed	Not assessed: no variant-specific ATM rescue result is documented for NM_000051.4:c.2638+11A>G.	cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	Not applicable: the ATM VCEP version 1.5 explicitly excludes BS4 from use.	cspec
BP1	N/A	Not applicable: c.2638+11A>G is intronic with protein consequence p.?, not a missense variant eligible for BP1.	cspec
BP2	Not assessed	Not assessed: no unaffected adult, paired pathogenic ATM variant, or confirmed cis/trans or homozygous observation is available to assign BP2 points.	cspec vcep_atm_pm3_bp2_1_5
BP3	N/A	Not applicable: the ATM VCEP v1.5 explicitly prohibits BP3, and this variant is an intronic single-nucleotide substitution rather than an in-frame repeat-region indel.	cspec
BP4	Met	Met, Supporting: SpliceAI maximum delta score is 0.00, meeting the ATM VCEP BP4 no-splice-impact threshold of ≤0.1.	cspec spliceai
BP5	N/A	Not applicable: the ATM VCEP explicitly excludes BP5 and provides no qualifying BP5-specific evidence for this variant.	cspec
BP6	N/A	Not applicable: ATM VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign assertion.	cspec clinvar
BP7	N/A	Not applicable: NM_000051.4:c.2638+11A>G is intronic, whereas BP7 is restricted to synonymous variants.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.