Variant classification summary

NM_000051.4:c.8047A>G

ATM · NP_000042.3:p.(Ile2683Val) · NM_000051.4

GRCh37: chr11:108205732 A>G · GRCh38: chr11:108335005 A>G

Gene: ATM Transcript: NM_000051.4

Final call

PM2 supporting BP4 supporting benign

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Ile2683Val)

gnomAD AF

8.057088812670206e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

This variant is a missense substitution (c.8047A>G, p.Ile2683Val) in ATM, assessed under the ClinGen HBOP VCEP v1.5.0 framework.

2

The variant is present in gnomAD v4.1 at a very low frequency (AF=0.00081%, 13/1,613,486 alleles, grpmax FAF=0.0005%), meeting the PM2_Supporting criterion (≤0.001% threshold).

3

Computational evidence supports a benign effect: REVEL score of 0.165 (≤0.249 threshold), BayesDel score of -0.311657, and SpliceAI predicts no splicing impact (max delta=0.00, ≤0.1), meeting BP4_Supporting. The VCEP supplementary computational meta-predictor (Suppl_TableS1, PMID 40580951) classifies this variant as Functional with High confidence.

4

No functional assay data (kinase activity or radiosensitivity rescue) are available for this variant, so PS3 and BS3 cannot be assessed.

5

No case-control studies, segregation data, or trans/homozygous observations in unaffected individuals were identified, leaving PS4, PP1, and BP2 unassessed.

6

ClinVar lists this variant as Uncertain significance (3 clinical laboratories) and Likely benign (1 clinical laboratory) with no expert panel submissions.

7

Applying the VCEP combining rules: PM2_Supporting (1 pathogenic supporting) and BP4_Supporting (1 benign supporting) yields a classification of Uncertain Significance - Conflicting Evidence per Rule 31.

Final determination: Rule31 in the Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as 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	N/A	This is a missense variant (NP_000042.3:p.Ile2683Val). PVS1 under the ATM VCEP v1.5.0 decision tree applies only to null variants (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion). Missense variants do not qualify.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not met	PS1 requires a different nucleotide change producing the same amino acid change (Ile2683Val) that has been established as pathogenic. Review of the VCEP supplementary table (Suppl_TableS1) and ClinVar shows no alternative nucleotide substitution at codon 2683 producing I2683Val (c.8047A>C/T both produce I2683L; c.8048T>C/G/A produce I2683T/R/K; c.8049A>G produces I2683M). No pathogenic variant with the identical amino acid change exists at this residue.	vcep_suppl_tables1_pmid_40580951 clinvar cspec
PS2	N/A	The ATM VCEP v1.5.0 explicitly states PS2 should not be used for AD or AR disease, as informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not assessed	No well-established functional assay data are available for this variant. The ATM VCEP PS3 rules require rescue assays demonstrating failure to rescue ATM-specific kinase activity and/or radiosensitivity. The VCEP supplementary functional assay spreadsheets (kinase activity and radiosensitivity) do not list this specific variant. The computational meta-predictor in Suppl_TableS1 (PMID 40580951) classifies c.8047A>G as 'Functional' (combined score -0.265, High confidence), which is a computational prediction, not a wet-lab functional assay suitable for PS3/BS3.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec oncokb
PS4	Not assessed	No case-control study with a p-value ≤0.05 and an odds ratio/relative risk ≥2 (or lower 95% CI ≥1.5) has been identified for this specific variant. The ATM VCEP limits PS4 to formal case-control studies; proband counting is not permitted for PS4_Moderate.	cspec clinvar
PS5	Not met	PS5 is not defined in the ATM VCEP v1.5.0 framework. Under generic ACMG/AMP rules, PS5 applies when a reputable source recently reports the variant as pathogenic without the evidence being independently evaluated. No reputable source reports this variant as pathogenic; ClinVar shows Uncertain significance (3 clinical laboratories) and Likely benign (1 clinical laboratory).	cspec clinvar
PM1	N/A	The ATM VCEP v1.5.0 explicitly states PM1 should not be used: benign and pathogenic variants are known to occur within the same domains, and germline mutational hotspots are not well defined at this time.	cspec
PM2	Met	This variant has a frequency of 0.00081% (8.06e-06, 13/1,613,486 alleles) in gnomAD v4.1, which is ≤0.001% meeting the ATM VCEP threshold for PM2_Supporting. The VCEP specifies PM2 should be applied at supporting strength only (not moderate).	gnomad_v4 cspec
PM5	N/A	The ATM VCEP v1.5.0 restricts PM5 to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) is applied. This is a missense variant, and the VCEP explicitly states: 'Do not use for missense changes.'	cspec pm5_candidates
PM6	N/A	The ATM VCEP v1.5.0 explicitly states PM6 should not be used for AD or AR disease, as informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not assessed	The ATM VCEP restricts PP1 to autosomal recessive (A-T) conditions where affected relatives must have both variants identified in the proband. No segregation data are available for this variant. For autosomal dominant conditions, the VCEP explicitly instructs not to use PP1 because co-segregation analysis in lower-penetrance genes can lead to false positive results.	cspec
PP2	N/A	The ATM VCEP v1.5.0 explicitly states PP2 should not be used because ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	For missense variants, the ATM VCEP requires a REVEL score >0.7333 to apply PP3. The REVEL score for this variant is 0.165, which does not meet the threshold. For splicing, SpliceAI max delta score is 0.00, which does not meet the ≥0.2 threshold. BayesDel score is -0.311657, also inconsistent with a damaging prediction.	revel spliceai bayesdel cspec
PP4	N/A	The ATM VCEP v1.5.0 explicitly states PP4 should not be used: for autosomal dominant disease, breast cancer has multiple genetic etiologies with no features distinguishing hereditary from sporadic causes; for autosomal recessive disease, such evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	The ATM VCEP v1.5.0 explicitly states PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The ATM VCEP requires a grpmax filtering allele frequency >0.5% in gnomAD v4 for BA1. The grpmax FAF for this variant in gnomAD v4.1 is 5e-06 (0.0005%), which is far below the 0.5% threshold.	gnomad_v4 cspec
BS1	Not met	The ATM VCEP requires a grpmax filtering allele frequency >0.05% in gnomAD v4 for BS1. The grpmax FAF for this variant in gnomAD v4.1 is 5e-06 (0.0005%), which is below the 0.05% threshold.	gnomad_v4 cspec
BS2	N/A	The ATM VCEP v1.5.0 explicitly states BS2 should not be used because ATM has incomplete penetrance.	cspec
BS3	Not assessed	No functional assay data are available showing that this variant rescues either ATM-specific features (e.g., phosphorylation of ATM-specific targets) or radiosensitivity. The VCEP supplementary functional assay spreadsheets do not include this variant. The computational meta-predictor in Suppl_TableS1 classifies the variant as 'Functional' (combined score -0.265, High confidence), but this is a computational prediction rather than a wet-lab functional assay suitable for BS3.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951 cspec
BS4	N/A	The ATM VCEP v1.5.0 states BS4 should not be used: for autosomal dominant conditions, co-segregation analysis can lead to false positive results; for autosomal recessive conditions, informative instances of lack of co-segregation in A-T families are too rare for weighting.	cspec
BP1	N/A	The ATM VCEP v1.5.0 explicitly states BP1 should not be used because missense pathogenic variants are known for ATM.	cspec
BP2	Not assessed	The ATM VCEP applies BP2 through the PM3/BP2 point table for observations of the variant in trans with a pathogenic variant or in homozygous state in unaffected individuals (≥18 years, no evidence of A-T). No such observations have been identified for this variant in the available evidence.	cspec vcep_atm_pm3_bp2_1_5
BP4	Met	This missense variant has a REVEL score of 0.165, which is ≤0.249, meeting the ATM VCEP BP4 threshold for missense variants. Additionally, SpliceAI predicts no splicing impact (max delta score = 0.00, which is ≤0.1), satisfying the splicing component. The VCEP supplementary table (Suppl_TableS1, PMID 40580951) also classifies this variant as 'Functional' (combined score -0.265, High confidence). BayesDel score of -0.311657 further supports a benign computational prediction.	revel spliceai bayesdel vcep_suppl_tables1_pmid_40580951 cspec
BP5	N/A	The ATM VCEP v1.5.0 explicitly states BP5 should not be used: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance, so it will naturally co-occur with other pathogenic variants more frequently.	cspec
BP6	N/A	The ATM VCEP v1.5.0 explicitly states BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 under the ATM VCEP applies to synonymous variants and deep intronic variants (further than +7 at donor or -21 at acceptor sites). This is a missense variant (p.Ile2683Val), not a synonymous or deep intronic substitution. The BP7(RNA) sub-rules are also for silent substitutions and intronic variants.	cspec

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