Variant classification summary

NM_000051.4:c.6814G>A

ATM · NP_000042.3:p.(Glu2272Lys) · NM_000051.4

GRCh37: chr11:108196791 G>A · GRCh38: chr11:108326064 G>A

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PS3 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Glu2272Lys)

gnomAD AF

1.1153107379639383e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 Supporting: direct prime-editing data classify the variant as Non-functional with Medium-high confidence.

2

BP4 Supporting: SpliceAI maximum delta 0.075 meets the VCEP no-predicted-impact threshold of ≤0.1.

Final determination: Under the ATM VCEP v1.6 framework, PS3 Supporting and BP4 Supporting satisfy no pathogenic or benign combination rule, so the call is VUS.

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.6814G>A is a missense substitution, whereas the ATM VCEP PVS1 rule is limited to null variants.	cspec
PS1	Not met	Not met: no previously established pathogenic ATM variant with the same p.Glu2272Lys amino acid change was identified, and the governing PS1 guide has no matching entry.	cspec vcep_atm_ps1_1_6 PMID:12673804
PS2	N/A	Not applicable: the ATM VCEP prohibits PS2 for AD or AR disease because informative de novo occurrences have not been observed.	cspec
PS3	Met	Met at Supporting: direct prime-editing data classify ATM c.6814G>A (E2272K) as Non-functional with Medium-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: one variant allele in 114 ALL cases versus zero in 138 controls is reported, but the required p-value, effect estimate, and lower 95% confidence interval are unavailable.	cspec PMID:12673804
PM1	N/A	Not applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined.	cspec
PM2	Not met	Not met: gnomAD v4.1 highest-subpopulation AF is 0.00267%, above the VCEP's <=0.001% PM2 threshold, with 2 African alleles.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: the reported germline observation lacks an A-T proband, a pathogenic ATM variant in trans, and phase information required for PM3 points.	cspec vcep_atm_pm3_bp2_1_6 PMID:12673804
PM4	N/A	Not applicable: p.(Glu2272Lys) is a missense substitution with no protein-length change, while the VCEP PM4 rule applies to stop-loss variants.	cspec
PM5	N/A	Not applicable: ATM VCEP PM5 excludes missense changes, including this p.Glu2272Lys variant, despite same-residue missense entries in Table S1.	cspec vcep_suppl_tables1_pmid_40580951 PMID:40580951
PM6	N/A	Not applicable: the ATM VCEP prohibits PM6 for AD or AR disease because informative de novo occurrences have not been observed.	cspec
PP1	Not assessed	Not assessed: the report describes one affected patient but provides no affected-relative segregation count, parental testing, or meiosis data for the PP1 threshold.	cspec PMID:12673804
PP2	N/A	Not applicable: the ATM VCEP states that ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	Not met: REVEL 0.686 is below >0.7333 and SpliceAI maximum delta 0.075 is below the ≥0.2 PP3 threshold.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
PP4	N/A	Not applicable: the VCEP prohibits PP4 for ATM-related breast cancer and incorporates ataxia-telangiectasia phenotype evidence into the PM3\|BP2 table.	cspec
PP5	N/A	Not applicable: the VCEP explicitly prohibits PP5, so the variant's ClinVar submissions cannot establish this criterion.	cspec
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8.03e-06 (0.000803%), below the VCEP's >0.5% BA1 threshold.	cspec gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 8.03e-06 (0.000803%), below the VCEP's >0.05% BS1 threshold.	cspec gnomad_v4 gnomad_v2
BS2	N/A	Not applicable: the ATM VCEP Version 1.6 explicitly marks BS2 as Not Applicable.	cspec
BS3	Not met	Not met: direct prime-editing data classify ATM c.6814G>A (E2272K) as Non-functional, providing no evidence that the variant rescues ATM function for BS3.	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 gives no BS4 weight because informative lack-of-co-segregation in A-T families is too rare.	cspec
BP1	N/A	Not applicable: BP1 is prohibited for ATM because missense pathogenic variants are known in this gene.	cspec
BP2	Not assessed	Not assessed: no unaffected adult observation, pathogenic ATM co-allele, or cis/trans phase is documented for the reported germline variant.	cspec vcep_atm_pm3_bp2_1_6 PMID:12673804
BP3	N/A	Not applicable: the ATM VCEP explicitly designates BP3 Not Applicable for this framework.	cspec
BP4	Met	Met at Supporting: SpliceAI maximum delta 0.075 meets the VCEP no-predicted-impact threshold of ≤0.1, despite REVEL 0.686 not meeting ≤0.249.	cspec revel spliceai vcep_suppl_tables1_pmid_40580951 PMID:40580951
BP5	N/A	Not applicable: the VCEP prohibits BP5 because multiple pathogenic variants may coexist without phenotype differences and ATM has low penetrance.	cspec
BP6	N/A	Not applicable: the VCEP explicitly prohibits BP6, so the variant's ClinVar classification cannot establish this criterion.	cspec
BP7	N/A	Not applicable: BP7 is limited to synonymous or deep intronic variants, whereas this variant is missense.	cspec

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