NM_000051.4:c.2873A>G

ATM · NP_000042.3:p.(Glu958Gly) · NM_000051.4

GRCh37: chr11:108141825 A>G · GRCh38: chr11:108271098 A>G

Gene: ATM Transcript: NM_000051.4

Final call

Benign

BS1 strong BS3 moderate BP2 strong BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Glu958Gly)

gnomAD AF

5.576166719950038e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

BS1_Strong: The variant is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.0752%, exceeding the ATM VCEP threshold of >0.05% for BS1. The variant has been observed on 90 alleles including one homozygous individual, with highest frequency in the South Asian population (0.091%).

BS3_Moderate: Comprehensive functional assessment of all ATM SNVs using prime editing and deep learning (PMID:40580951) classifies p.Glu958Gly as 'Functional' with high confidence. The variant rescues both ATM-specific phosphorylation activity and radiosensitivity, meeting VCEP criteria for BS3_Moderate.

BP2_Strong: c.2873A>G has been observed in cis with a known pathogenic ATM variant (c.5932G>T, p.Glu1978*) on the same allele, corresponding to -4.0 points (BP2_Strong) under the ATM VCEP PM3/BP2 table.

BP4_Supporting: REVEL score of 0.121 is below the VCEP benign threshold of ≤0.249. BayesDel score of -0.224 is consistent with a benign prediction. SpliceAI predicts no significant splice impact (max delta 0.19).

No pathogenic criteria were met: PVS1 is not applicable (missense variant). PS1 is not met (no same amino acid change classified as pathogenic at codon 958). PS3 is not met (functional studies show normal, not damaging, effect). PM2 is not met (AF=0.00558% exceeds ≤0.001% VCEP threshold). PP3 is not met (REVEL=0.121 below >0.7333 threshold; SpliceAI=0.19 below ≥0.2 threshold).

Final determination: Rule16 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 Benign.

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	Missense variant (p.Glu958Gly); PVS1 is reserved for null variants (nonsense, frameshift, canonical splice, initiation codon, exon deletion) per the ATM PVS1 Decision Tree. A missense substitution does not qualify.	pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	Not met	No known pathogenic or likely pathogenic variant with the same amino acid change (p.Glu958Gly) has been identified. Other nucleotide substitutions at codon 958 produce different amino acid changes (p.Glu958Val, p.Glu958Ala), which are not the same amino acid substitution required for PS1.	vcep_atm_ps1_1_5 vcep_suppl_tables1_pmid_40580951
PS2	N/A	VCEP states do not use for AD or AR disease; informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
PS3	Not met	Well-established functional studies demonstrate normal ATM kinase activity and normal radiosensitivity for p.Glu958Gly, supporting a benign functional effect rather than a damaging one. The variant is classified as 'Functional' with high confidence in the ATM VCEP functional assessment dataset (PMID:40580951).	vcep_suppl_tables1_pmid_40580951 PMID:40580951
PS4	Not met	No case-control study or large case series demonstrating statistically significant enrichment of c.2873A>G in affected individuals compared to controls has been identified. The VCEP PS4 rule requires p≤0.05 AND (OR≥2 OR lower 95% CI ≥1.5).	gnomad_v4 clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP criterion and is not defined in the ATM VCEP v1.5.0 framework.
PM1	N/A	VCEP states do not use: benign and pathogenic variants are known to occur within the same ATM domains and germline mutational hotspots are not well defined at this time.
PM2	Not met	gnomAD v4.1 allele frequency is 5.58×10⁻⁵ (0.00558%, 90/1,614,012 alleles), which exceeds the VCEP PM2_Supporting threshold of ≤0.001% (≤1×10⁻⁵).	gnomad_v4
PM5	N/A	VCEP PM5 rule applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or splice variants with PVS1_Strength(RNA). Missense changes are explicitly excluded: 'Do not use for missense changes.'	pm5_candidates
PM6	N/A	VCEP states do not use for AD or AR disease: informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
PP1	Not met	No published co-segregation data for c.2873A>G in families with multiple affected members has been identified. No LOD score is available.
PP2	N/A	VCEP states do not use: ATM does not have a defined low rate of missense benign variation.
PP3	Not met	REVEL score is 0.121, well below the VCEP PP3 threshold of >0.7333 for missense variants. SpliceAI max delta score is 0.19, below the splicing threshold of ≥0.2.	revel spliceai
PP4	N/A	VCEP states do not use: AD condition has multiple genetic etiologies; AR condition phenotype evidence is built into the PM3/BP2 table.
PP5	N/A	VCEP states this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BA1	Not met	gnomAD v4.1 grpmax filtering allele frequency is 0.0752% (FAF=0.000752), which does not exceed the VCEP BA1 threshold of >0.5%.	gnomad_v4
BS1	Met	gnomAD v4.1 grpmax filtering allele frequency is 0.0752% (FAF=0.000752), exceeding the VCEP BS1 threshold of >0.05%. The variant is present on 90 alleles including one homozygous individual, indicating it is more common than expected for a highly penetrant ATM pathogenic variant.	gnomad_v4
BS2	N/A	VCEP states do not use: ATM has incomplete penetrance.
BS3	Met	Comprehensive functional assessment of all ATM SNVs using prime editing and deep learning (PMID:40580951) classifies c.2873A>G (p.Glu958Gly) as 'Functional' with high confidence (combined score -0.866). The variant rescues both ATM-specific phosphorylation activity and radiosensitivity, meeting VCEP BS3_Moderate criteria. Prior independent studies (Barone et al. 2009, Mitui et al. 2009) also reported normal kinase activity and radiosensitivity for this variant.	vcep_suppl_tables1_pmid_40580951 PMID:40580951
BS4	N/A	VCEP states do not use: co-segregation analysis in low-penetrance genes can lead to false positive results (AD); informative instances of lack of co-segregation in A-T families are too rare (AR).
BP1	N/A	VCEP states do not use: missense pathogenic variants are known for ATM.
BP2	Met	c.2873A>G has been observed in cis with a known pathogenic ATM variant (c.5932G>T, p.Glu1978*) on the same allele. Under the ATM VCEP PM3/BP2 table, confirmed cis configuration with a pathogenic variant in a recessive gene assigns -4.0 points, corresponding to BP2_Strong.	vcep_atm_pm3_bp2_1_5
BP4	Met	REVEL score is 0.121, below the VCEP BP4 missense threshold of ≤0.249. BayesDel score is -0.224, consistent with a benign computational prediction. SpliceAI predicts no significant splice impact (max delta 0.19).	revel bayesdel spliceai
BP5	N/A	VCEP states do not use: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; ATM has low penetrance and will naturally occur with other pathogenic variants more frequently.
BP6	N/A	VCEP states this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
BP7	N/A	BP7 applies to synonymous and deep intronic variants only. This is a missense variant (c.2873A>G, p.Glu958Gly) resulting in an amino acid substitution, not a silent substitution.
BP3	N/A	VCEP states do not use. BP3 applies to in-frame deletions/insertions in repetitive regions without known function; this is a single-nucleotide missense substitution.
PM3	N/A	Skipped per case adjudication directive; PM3 trans observation data was not assessed as part of this criteria review.
PM4	N/A	VCEP PM4 rule applies to stop-loss variants only. This is a missense substitution (c.2873A>G, p.Glu958Gly), not a stop-loss variant.

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