NM_000051.4:c.7486G>C

ATM · NP_000042.3:p.(Gly2496Arg) · NM_000051.4

GRCh37: chr11:108201119 G>C · GRCh38: chr11:108330392 G>C

Gene: ATM Transcript: NM_000051.4

Final call

PM2 supporting BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Gly2496Arg)

gnomAD AF

3.717246412547441e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.7486G>C (p.Gly2496Arg) is a missense variant in ATM exon 50.

This variant is extremely rare in population databases: present in gnomAD v4.1 at an allele frequency of 0.00037% (6/1,614,098 alleles, 0 homozygotes), meeting the VCEP threshold for PM2_Supporting.

Multiple lines of computational evidence suggest a benign effect: REVEL score is 0.189 (meeting the VCEP BP4 threshold of ≤0.249), BayesDel score is negative (-0.183511), and SpliceAI predicts no splicing impact (max delta 0.04). BP4_Supporting is applied.

The ATM VCEP supplementary in silico meta-predictor (Suppl_TableS1, PMID:40580951) classifies this variant as 'Functional' with High confidence (Combined score 0.962), consistent with the benign computational evidence.

This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (Variation ID: 569749).

PVS1, PS1, PM1, PM5, PM6, PS2, PP1, PP2, PP4, PP5, BS2, BS4, BP1, BP5, BP6, and BP7 are not applicable per ATM VCEP v1.5.0 specifications.

No variant-specific experimental functional studies, case-control data, or segregation data were identified for this variant.

Applying the ATM VCEP v1.5.0 classification framework: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point). Per the generic ACMG/AMP 2015 combination rules (Rule 31), one pathogenic supporting criterion and one benign supporting criterion result in conflicting evidence, yielding an overall classification of Uncertain Significance.

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	PVS1 is applicable only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, exon deletions). NM_000051.4:c.7486G>C is a missense variant (p.Gly2496Arg) and does not meet the variant-type prerequisites for PVS1 under the ATM VCEP PVS1 decision tree.	pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	Not met	PS1 requires a previously established pathogenic or likely pathogenic variant causing the same amino acid change. The only other variant at this residue yielding Gly2496Arg is NM_000051.4:c.7486G>A, which is classified as Uncertain significance in ClinVar and is not an established P/LP variant. No P/LP variant with the same amino acid change was identified.	vcep_atm_ps1_1_5 vcep_suppl_tables1_pmid_40580951
PS2	N/A	PS2 is not applicable per ATM VCEP v1.5.0: informative de novo occurrences have not yet been observed for ATM and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not assessed	No variant-specific experimental functional studies (well-established in vitro or in vivo assays) were identified for NM_000051.4:c.7486G>C. The VCEP supplementary spreadsheet (Suppl_TableS1, PMID:40580951) provides an in silico meta-prediction classifying this variant as 'Functional' (Combined score 0.962, High confidence), but this represents computational prediction rather than experimental functional evidence. No published functional assay data (kinase activity, radiosensitivity, or ATM-specific phosphorylation rescue) were found for this variant.	vcep_suppl_tables1_pmid_40580951 oncokb
PS4	Not met	PS4 requires case-control studies demonstrating statistically significant enrichment of the variant in affected individuals (p≤0.05, OR/HR/RR ≥2 or lower 95% CI ≥1.5). None of the publications associated with this case provide case-control data for this variant. The ClinVar-associated PMIDs are general reviews, guidelines, or methodological papers that do not contain variant-specific prevalence or enrichment data.	cspec
PS5	N/A	PS5 is not a standard ACMG/AMP criterion. No such criterion exists in the ACMG/AMP 2015 guidelines or the ATM VCEP v1.5.0 specifications.
PM1	N/A	PM1 is not applicable per ATM VCEP v1.5.0. The VCEP states: 'Do not use: 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	NM_000051.4:c.7486G>C is extremely rare in population databases. In gnomAD v4.1, the variant is present at an allele frequency of 0.00037% (6/1,614,098 alleles, 0 homozygotes), with a grpmax filtering AF of 1.83e-06. This frequency (≤0.001%) meets the ATM VCEP threshold for PM2_Supporting.	gnomad_v4 cspec
PM5	N/A	PM5 per ATM VCEP v1.5.0 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants meeting specific criteria. The VCEP explicitly states: 'Do not use for missense changes.' NM_000051.4:c.7486G>C is a missense variant.	cspec pm5_candidates
PM6	N/A	PM6 is not applicable per ATM VCEP v1.5.0: '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.'	cspec
PP1	Not met	PP1 requires co-segregation of the variant with disease in affected family members. For ATM (AR condition), this requires both variants to be identified in affected relatives. No segregation data were identified in any of the reviewed publications or evidence sources.
PP2	N/A	PP2 is not applicable per ATM VCEP v1.5.0: 'Do not use: ATM does not have a defined low rate of missense benign variation.'	cspec
PP3	Not met	PP3 for missense variants under ATM VCEP requires REVEL score >0.7333. The REVEL score for this variant is 0.189, which does not meet this threshold. SpliceAI max delta score is 0.04 (<0.2), indicating no predicted splicing impact. Multiple lines of computational evidence do not support a deleterious effect.	revel bayesdel spliceai cspec
PP4	N/A	PP4 is not applicable per ATM VCEP v1.5.0: for autosomal dominant (breast cancer), do not use due to genetic heterogeneity; for autosomal recessive, such evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	PP5 is not applicable per ATM VCEP v1.5.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BA1	Not met	BA1 requires grpmax filtering AF >0.5% in gnomAD v4. The variant's grpmax FAF is 1.83e-06 (0.000183%), far below the 0.5% threshold.	gnomad_v4 cspec
BS1	Not met	BS1 requires grpmax filtering AF >0.05% in gnomAD v4. The variant's grpmax FAF is 1.83e-06 (0.000183%), far below the 0.05% threshold.	gnomad_v4 cspec
BS2	N/A	BS2 is not applicable per ATM VCEP v1.5.0: 'Do not use: ATM has incomplete penetrance.'	cspec
BS3	Not assessed	No variant-specific experimental functional studies demonstrating no damaging effect were identified for NM_000051.4:c.7486G>C. The VCEP supplementary spreadsheet (Suppl_TableS1, PMID:40580951) classifies this variant as 'Functional' (Combined score 0.962, High confidence) based on in silico meta-prediction, but this computational prediction does not constitute well-established in vitro or in vivo functional evidence as required for BS3. No published functional rescue data (kinase activity, radiosensitivity) were identified for this variant.	vcep_suppl_tables1_pmid_40580951 oncokb
BS4	N/A	BS4 is not applicable per ATM VCEP v1.5.0: for AD (cancer), co-segregation analysis in low-penetrance genes can lead to false positives; for AR (A-T), informative instances of lack of co-segregation are too rare to be considered for weight.	cspec
BP1	N/A	BP1 is not applicable per ATM VCEP v1.5.0: 'Do not use: Missense pathogenic variants are known for ATM.'	cspec
BP2	Not assessed	BP2 requires observation of the variant in trans with a pathogenic variant in an unaffected individual (≥18 years, no evidence of A-T). No such data were identified in the available evidence. No proband data for PM3/BP2 point assignment were found.	vcep_atm_pm3_bp2_1_5
BP3	N/A	BP3 is not applicable per ATM VCEP v1.5.0. This criterion applies to in-frame deletions/insertions in repetitive regions without known function; not relevant to a missense substitution.	cspec
BP4	Met	BP4 for missense variants under ATM VCEP requires REVEL score ≤0.249. The REVEL score for NM_000051.4:c.7486G>C is 0.189, meeting this threshold. Additionally, BayesDel score is negative (-0.183511) and SpliceAI max delta is 0.04 (≤0.1), indicating no predicted splicing impact. Multiple lines of computational evidence suggest no damaging effect on the gene product.	revel bayesdel spliceai cspec
BP5	N/A	BP5 is not applicable per ATM VCEP v1.5.0: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype. In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently.'	cspec
BP6	N/A	BP6 is not applicable per ATM VCEP v1.5.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'	cspec
BP7	N/A	BP7 applies to synonymous variants and deep intronic variants. NM_000051.4:c.7486G>C is a missense variant (p.Gly2496Arg) and does not meet the variant-type requirements for BP7.	cspec
PM3	N/A	PM3 is skipped per adjudication instructions. No trans-phase data were collected for PM3/BP2 point assignment in this assessment run.
PM4	N/A	PM4 is skipped per adjudication instructions. NM_000051.4:c.7486G>C is a missense substitution; PM4 applies only to in-frame deletions/insertions and stop-loss variants per ATM VCEP.	cspec

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