LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-13
Case ID: NM_000051.4_c.858A_G_20261013_193728
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.858A>G

ATM  · NP_000042.3:p.(Gln286=)  · NM_000051.4
GRCh37: chr11:108115710 A>G  ·  GRCh38: chr11:108244983 A>G
Gene: ATM Transcript: NM_000051.4
Final call
VUS
PP3 supporting BS3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Gln286=)
gnomAD AF
6.201973467957504e-06 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PP3 supporting: SpliceAI predicts a delta of 0.208 for the silent c.858A>G, at or above the ATM Expert Panel's 0.2 splice threshold.
2
BS3 supporting: a direct prime-editing measurement scored the variant Functional (0.024), indicating retained ATM function.
Final determination: Under the ATM Expert Panel v1.6 criteria-combination framework, one supporting pathogenic criterion plus one supporting benign criterion satisfies Rule31, which yields Uncertain Significance - Conflicting Evidence, i.e. a variant of uncertain significance.
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.858A>G is synonymous (p.Gln286=), causing no protein-length change and belonging to none of the PVS1 null-variant classes.
cspec vcep_atm_pvs1_1_5 vcep_suppl_tables1_pmid_40580951 spliceai PMID:25741868
PS1 Not met Not met: synonymous p.Gln286= has no established P/LP reference variant at c.858 or within exon 7's splice motif to satisfy the PS1 prerequisite.
cspec vcep_atm_ps1_1_6 vcep_atm_ps1_1_5 spliceai clinvar
PS2 N/A Not applicable: the ATM VCEP v1.6 specification lists PS2 as Not Applicable, so de novo evidence cannot contribute to this variant's classification.
cspec
PS3 Not met Not met: the only direct functional measurement, a prime-editing screen score of 0.024, classified c.858A>G as Functional, and no VCEP-approved assay reports it.
cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4 Not met Not met: no case-control odds ratio, hazard ratio or relative-risk estimate exists for this variant to compare against the VCEP's p<=.05 and OR/HR/RR>=2 thresholds.
cspec PMID:17508274 PMID:24418350
PM1 N/A Not applicable: the governing ATM VCEP specification explicitly disables PM1, and no VCEP-approved ATM critical-domain table is defined.
cspec
PM2 Not met Not met: the highest gnomAD ancestry frequency, 0.00808% in African/African American (v2.1, 2/24,766 alleles), exceeds the VCEP PM2 threshold of 0.001% and the n=1 exception does not apply.
cspec gnomad_v2 gnomad_v4
PM3 Not met Not met: no A-T proband carries c.858A>G in trans with a P/LP ATM variant, giving 0 points versus the 1.0-point PM3_Supporting threshold.
vcep_atm_pm3_bp2_1_6 vcep_atm_pm3_bp2_1_5 cspec clinvar gnomad_v2 gnomad_v4
PM4 N/A Not applicable: ATM's VCEP limits PM4 to stop-loss variants, and p.Gln286= is synonymous with no change to the 3058-residue protein length.
cspec vcep_suppl_tables1_pmid_40580951 PMID:25741868
PM5 Not met Not met: p.Gln286= is not a truncating PVS1 variant eligible under the ATM VCEP's PM5 rule, and no P/LP missense variant exists at residue 286.
cspec pm5_candidates
PM6 N/A Not applicable: the ATM VCEP v1.6 specification lists PM6 (assumed de novo) as Not Applicable for ATM.
cspec
PP1 Not assessed Not assessed: no pedigree or segregation data exist (zero informative meioses), so PP1's >=1-affected-relative threshold cannot be evaluated.
cspec
PP2 N/A Not applicable: the ATM VCEP specification lists PP2 as Not Applicable, and c.858A>G is a synonymous, not missense, variant.
cspec
PP3 Met Met at supporting: synonymous c.858A>G has SpliceAI max delta 0.208, at or above the ATM VCEP PP3 splice threshold of 0.2.
cspec spliceai vcep_suppl_tables1_pmid_40580951 pvs1_variant_assessment
PP4 N/A Not applicable: the ATM VCEP v1.6 specification explicitly lists PP4 as Not Applicable for this gene.
cspec
PP5 Not met Not met: ClinVar VCV000185146 is 1-star conflicting laboratory classifications with no expert-panel submission, so the expert-assertion requirement for PP5 is absent.
cspec clinvar
BA1 Not met Not met: the highest gnomAD ancestry frequency is 0.00808% (African/African American, v2.1), far below the VCEP stand-alone BA1 threshold of 0.5%.
cspec gnomad_v2 gnomad_v4
BS1 Not met Not met: the highest gnomAD ancestry frequency is 0.00808% (African/African American, v2.1), below the VCEP BS1 strong threshold of 0.05%.
cspec gnomad_v2 gnomad_v4
BS2 N/A Not applicable: BS2 is designated Not Applicable in the ATM HBOP VCEP v1.6 specification.
cspec
BS3 Met Met at supporting strength: directly measured prime-editing score 0.024 places c.858A>G in the assay's Functional band (>= -0.912), indicating retained ATM function.
cspec vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4 N/A Not applicable: the ATM VCEP v1.6 specification lists BS4 (non-segregation with disease) as Not Applicable for ATM.
cspec
BP1 N/A Not applicable: the ATM VCEP specification lists BP1 as Not Applicable, and c.858A>G is a synonymous rather than truncating variant.
cspec
BP2 Not met Not met: no unaffected carrier of c.858A>G in trans with a P/LP ATM variant and zero gnomAD homozygotes, scoring 0 versus the -1.0-point BP2 threshold.
vcep_atm_pm3_bp2_1_6 vcep_atm_pm3_bp2_1_5 cspec clinvar gnomad_v2 gnomad_v4 gnomad_canada
BP3 N/A Not applicable: the ATM VCEP declares BP3 not applicable, and a single-nucleotide synonymous change is not an in-frame repeat-region indel.
cspec vcep_suppl_tables1_pmid_40580951 PMID:25741868
BP4 Not met Not met: SpliceAI max delta 0.208 exceeds the ATM VCEP BP4 threshold of <=0.1 for no predicted splice impact.
cspec spliceai vcep_suppl_tables1_pmid_40580951
BP5 N/A Not applicable: the ATM VCEP v1.6 specification explicitly lists BP5 as Not Applicable for this gene.
cspec
BP6 Not met Not met: ClinVar VCV000185146 has no expert-panel classification (1-star, conflicting), so the aggregate Likely-benign label cannot trigger BP6.
cspec clinvar
BP7 Not met Not met: c.858A>G is synonymous and in BP7 scope, but SpliceAI predicts a new acceptor site (max delta 0.208), so no splice impact cannot be asserted.
cspec spliceai PMID:25741868
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