Variant classification summary

NM_000051.4:c.2552A>G

ATM · NP_000042.3:p.(Asp851Gly) · NM_000051.4

GRCh37: chr11:108137983 A>G · GRCh38: chr11:108267256 A>G

Gene: ATM Transcript: NM_000051.4

Final call

Likely Benign

BS3 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Asp851Gly)

gnomAD AF

1.4869980607066958e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS3 supporting: direct prime-editing screening classified p.Asp851Gly as Functional with High confidence.

2

BP4 supporting: REVEL 0.099 meets the ATM VCEP missense threshold of <=0.249.

Final determination: ATM VCEP Version 1.5 Rule19 classifies a variant as Likely Benign when at least two benign supporting criteria are met; BS3 supporting and BP4 supporting satisfy this rule.

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	N/A	Not applicable: c.2552A>G is a missense substitution producing p.Asp851Gly, outside the ATM VCEP's PVS1 null-variant mechanisms.	cspec vcep_atm_pvs1_1_5 pvs1_variant_assessment
PS1	Not met	Not met: no established pathogenic or likely pathogenic comparator for p.Asp851Gly was identified in the governing ATM PS1 evidence.	cspec vcep_atm_ps1_1_5
PS2	N/A	Not applicable: ATM VCEP v1.5 excludes PS2 because informative de novo observations are not established for ATM-related conditions.	cspec
PS3	Not assessed	Not assessed: the direct screen classified c.2552A>G as Functional, High confidence, not as an abnormal ATM-specific readout supporting PS3.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not assessed	Not assessed: no variant-specific case-control p-value, effect estimate, or confidence interval is available to compare with the VCEP PS4 thresholds.	cspec
PM1	Not met	Not met: ATM has no authoritative domain-table entry, and residue 851 has no documented significant hotspot evidence supporting PM1.	cspec
PM2	Not met	Not met: gnomAD v4.1 combined AF is 0.00149%, above the ATM VCEP PM2 cutoff of at or below 0.001%.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no affected A-T proband, phase, trans partner, or homozygous observation was available to assign PM3 points under the ATM VCEP table.	vcep_atm_pm3_bp2_1_5 cspec gnomad_v4
PM4	N/A	Not applicable: p.Asp851Gly is a missense substitution, whereas ATM VCEP PM4 is specified only for stop-loss variants.	cspec
PM5	N/A	Not applicable: p.Asp851Gly is missense, whereas the ATM PM5 rule applies to qualifying truncating or splice variants.	cspec pm5_candidates
PM6	N/A	Not applicable: ATM VCEP v1.5 excludes PM6 because assumed de novo status is not informative for ATM disease.	cspec
PP1	Not assessed	Not assessed: zero affected relatives or informative segregation meioses are documented, so the VCEP's 1/2/3-relative PP1 thresholds cannot be applied.	cspec
PP2	N/A	Not applicable: the ATM VCEP explicitly designates PP2 as Not Applicable.	cspec
PP3	Not met	Not met: REVEL 0.099 and SpliceAI maximum delta 0.074 are below the ATM VCEP PP3 thresholds of >0.7333 and >=0.2.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951
PP4	N/A	Not applicable: the ATM VCEP disallows separate PP4 use because the relevant phenotypes are nonspecific or incorporated into PM3/BP2.	cspec
PP5	Not met	Not met: ClinVar reports zero expert-panel submissions for this exact variant, so ordinary laboratory and aggregate classifications cannot support PP5.	clinvar cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00103%, below the ATM VCEP BA1 threshold of greater than 0.5%.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 0.00103%, below the ATM VCEP BS1 threshold of greater than 0.05%.	cspec gnomad_v4
BS2	N/A	Not applicable: the ATM VCEP marks BS2 as not applicable, despite zero homozygotes in gnomAD v4.1.	cspec gnomad_v4
BS3	Met	Met, Supporting: direct prime-editing screen classified c.2552A>G as Functional with High confidence and Combined_score 0.586774271783898, pending assay-approval review.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 cspec
BS4	N/A	Not applicable: ATM VCEP v1.5 assigns no BS4 weight because informative non-segregation is too rare and cancer phenocopies confound interpretation.	cspec
BP1	N/A	Not applicable: the ATM VCEP explicitly designates BP1 as Not Applicable.	cspec
BP2	Not assessed	Not assessed: no unaffected adult with a pathogenic ATM variant in trans or eligible homozygous observation was available for BP2 scoring.	vcep_atm_pm3_bp2_1_5 cspec
BP3	N/A	Not applicable: the ATM VCEP marks BP3 not applicable, and p.Asp851Gly is not a repetitive-region in-frame insertion or deletion.	cspec
BP4	Met	Met, supporting: REVEL 0.099 is below the ATM VCEP BP4 missense threshold of <=0.249.	cspec revel vcep_suppl_tables1_pmid_40580951
BP5	N/A	Not applicable: the ATM VCEP explicitly prohibits BP5 because alternate pathogenic variants can co-occur without a distinguishable phenotype.	cspec
BP6	Not met	Not met: the exact variant has no ClinVar expert-panel Benign or Likely benign classification, only a single-laboratory Likely benign submission.	clinvar cspec
BP7	N/A	Not applicable: c.2552A>G produces the missense substitution p.Asp851Gly, not a synonymous variant.	cspec vcep_suppl_tables1_pmid_40580951

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.