Variant classification summary

NM_000051.4:c.4997A>C

ATM · NP_000042.3:p.(Glu1666Ala) · NM_000051.4

GRCh37: chr11:108168101 A>C · GRCh38: chr11:108297374 A>C

Gene: ATM Transcript: NM_000051.4

Final call

PM2 supporting PP3 supporting BS3 moderate BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Glu1666Ala)

gnomAD AF

1.8593351017676078e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.4997A>C (p.Glu1666Ala) is a missense variant at an extremely low population frequency (gnomAD v4.1 AF = 1.86e-06, 3/1,613,480 alleles).

2

Functional assay data curated by the ClinGen HBOP VCEP demonstrate that p.Glu1666Ala rescues both ATM kinase activity and cellular radiosensitivity to wild-type levels, consistent with a benign functional effect (BS3_Moderate).

3

Multiple in silico predictors support a benign effect: REVEL 0.054 (≤0.249, BP4_Supporting), BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033.

4

SpliceAI predicts a possible splicing impact (max delta 0.24, ≥0.2) qualifying for PP3_Supporting under the VCEP splicing prediction rule, though this is modestly above threshold and conflicts with the benign in silico and functional evidence.

5

The variant is absent from COSMIC and no case-control or segregation studies are available. Six publications provided by ClinVar were reviewed in full text; none mention NM_000051.4:c.4997A>C specifically.

Final determination: Rule31 in the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 v1.5 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	PVS1 is applicable only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, or exon deletions). NM_000051.4:c.4997A>C is a missense variant (p.Glu1666Ala) and does not fall into any PVS1-eligible variant class per the ATM VCEP PVS1 decision tree.	pvs1_variant_assessment
PS1	Not met	PS1 requires a (likely) pathogenic variant at the same nucleotide position with a different nucleotide change. At c.4997, alternative changes c.4997A>T (p.E1666V) and c.4997A>G (p.E1666G) exist but neither is classified as pathogenic or likely pathogenic in ClinVar. No qualifying PS1 comparator is identified.	clinvar vcep_suppl_tables1_pmid_40580951
PS2	N/A	The ATM HBOP VCEP v1.5 specifies PS2 as Not Applicable: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.
PS3	Not met	PS3 requires experimental evidence of a damaging effect on ATM function. The ATM VCEP functional assay data (Suppl_TableS1, PMIDs 18634022, 19431188, 11805335) classifies c.4997A>C (p.E1666A) as 'Functional' (combined score 0.456, High confidence), indicating the variant retains normal kinase activity and radiosensitivity rescue. No evidence of damaging functional effect exists; the functional data support benign effect (see BS3).	vcep_suppl_tables1_pmid_40580951 vcep_atm_pvs1_1_5
PS4	Not met	The ATM VCEP requires case-control studies with p-value ≤0.05 AND (OR/HR/RR ≥2 OR lower 95% CI ≥1.5) for PS4. No such case-control studies have been identified for NM_000051.4:c.4997A>C. The variant is absent from COSMIC and has no enrichment data in affected vs. control populations.	clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP criterion. No VCEP or generic ACMG rule exists for this code.
PM1	N/A	The ATM HBOP VCEP v1.5 specifies PM1 as Not Applicable: benign and pathogenic variants occur within the same domains and germline mutational hotspots are not well defined for ATM at this time.
PM2	Met	This variant is present in gnomAD v4.1 at an extremely low frequency (AF=1.86e-06; 3/1,613,480 alleles, 0 homozygotes; grpmax FAF=6.8e-07). Per ATM VCEP v1.5, frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting.	gnomad_v4
PM5	N/A	The ATM VCEP PM5 rule applies only to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_Strength(RNA). The VCEP explicitly states: 'Do not use for missense changes.' NM_000051.4:c.4997A>C is a missense variant and is not eligible for PM5.	pm5_candidates
PM6	N/A	The ATM HBOP VCEP v1.5 specifies PM6 as Not Applicable: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.
PP1	Not met	The ATM VCEP applies PP1 only for autosomal recessive (ataxia telangiectasia) conditions, requiring segregation in affected relatives. No segregation data are available for this variant.
PP2	N/A	The ATM HBOP VCEP v1.5 specifies PP2 as Not Applicable: ATM does not have a defined low rate of missense benign variation.
PP3	Met	SpliceAI predicts a possible splicing impact (max delta score = 0.24). Per ATM VCEP v1.5, SpliceAI ≥0.2 qualifies for PP3_Supporting for missense variants via the splicing prediction route. The REVEL score (0.054) does NOT independently support PP3 via the missense pathway (threshold >0.7333).	spliceai
PP4	N/A	The ATM HBOP VCEP v1.5 specifies PP4 as Not Applicable: breast cancer has multiple genetic etiologies (genetic heterogeneity) and no features readily distinguish hereditary from sporadic causes; for ataxia telangiectasia, such evidence is built into the PM3/BP2 table.
PP5	N/A	The ATM HBOP VCEP v1.5 specifies PP5 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
BA1	Not met	The ATM VCEP BA1 threshold is grpmax Filtering AF >0.5% in gnomAD v4. The grpmax FAF for this variant is 6.8e-07 (0.000068%), far below the 0.5% threshold. BA1 is not met.	gnomad_v4
BS1	Not met	The ATM VCEP BS1 threshold is grpmax Filtering AF >0.05% in gnomAD v4. The grpmax FAF for this variant is 6.8e-07 (0.000068%), far below the 0.05% threshold. BS1 is not met.	gnomad_v4
BS2	N/A	The ATM HBOP VCEP v1.5 specifies BS2 as Not Applicable: ATM has incomplete penetrance.
BS3	Met	Functional assay data curated by the ATM HBOP VCEP (Suppl_TableS1, based on kinase activity assays: Mitui 2009 PMID 18634022, Barone 2009 PMID 19431188; and radiosensitivity assays: Mitui 2009, Scott 2002 PMID 11805335) classify NM_000051.4:c.4997A>C (p.E1666A) as 'Functional' with High confidence (combined score 0.456). The variant rescues both ATM-specific kinase activity (phosphorylation of ATM targets) and cellular radiosensitivity, satisfying the VCEP BS3_Moderate threshold: variant rescues both an ATM-specific feature AND radiosensitivity.	vcep_suppl_tables1_pmid_40580951 vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BS4	N/A	The ATM HBOP VCEP v1.5 specifies BS4 as Not Applicable: co-segregation analysis in low-penetrance genes can produce false positives; informative instances of lack of co-segregation in A-T families are too rare to be considered.
BP1	N/A	The ATM HBOP VCEP v1.5 specifies BP1 as Not Applicable: missense pathogenic variants are known for ATM.
BP2	Not met	BP2 requires observation of the variant in trans with a P/LP variant in an unaffected individual (≥18 years, no evidence of A-T) or homozygous in an unaffected individual per the ATM PM3/BP2 table. No such data are available for this variant.
BP4	Met	The REVEL score for this variant is 0.054, which is ≤0.249, meeting the ATM VCEP BP4_Supporting threshold for missense variants. Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033. The SpliceAI delta (0.24) does NOT support BP4 via the splicing route (threshold ≤0.1).	revel bayesdel vcep_suppl_tables1_pmid_40580951
BP5	N/A	The ATM HBOP VCEP v1.5 specifies BP5 as Not Applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance in the general population.
BP6	N/A	The ATM HBOP VCEP v1.5 specifies BP6 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation.
BP7	N/A	BP7 per the ATM VCEP applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). NM_000051.4:c.4997A>C is a missense variant, not synonymous. BP7(RNA) requires observed lack of aberrant RNA splicing defect, which has not been assessed for this variant.

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