Variant classification summary

NM_000051.4:c.7913G>A

ATM · NP_000042.3:p.(Trp2638Ter) · NM_000051.4

GRCh37: chr11:108203613 G>A · GRCh38: chr11:108332886 G>A

Gene: ATM Transcript: NM_000051.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Trp2638Ter)

gnomAD AF

7.441463587058303e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.7913G>A is a nonsense variant (p.Trp2638Ter) in exon 53 of ATM, a gene for which loss of function is a well-established mechanism of disease. The premature termination codon is upstream of p.Arg3047, and NMD is expected. PVS1 is applied at very strong strength per the ClinGen HBOP VCEP ATM PVS1 decision tree.

2

This variant is present at extremely low frequency in gnomAD v4.1 (AF = 0.00074%, 12/1,612,586 alleles, 0 homozygotes; grpmax FAF = 0.007%), meeting the VCEP PM2_Supporting threshold of ≤0.001%.

3

The variant produces a premature termination codon at p.Trp2638, upstream of the most C-terminal known pathogenic variant p.Arg3047, satisfying the VCEP PM5_Supporting truncation cutoff rule.

4

This variant has been observed in the literature in multiple unrelated AT patients: as a compound heterozygous mutation (with c.3802delG) in Brazilian AT patients (Coutinho et al. 2004, PMID:15039971), as a homozygous mutation in a consanguineous African-Brazilian patient with classical AT (Demuth et al. 2011, PMID:21965147), and as a homozygous mutation in an AT proband (Family 605) studied for gamma-H2AX radiosensitivity (Kato et al. 2006, PMID:16953663). These observations are consistent with biallelic pathogenicity for ataxia telangiectasia.

5

The VCEP combination rule 4 is satisfied: 1 Very Strong criterion (PVS1) + ≥2 Supporting criteria (PM2_Supporting, PM5_Supporting) → Pathogenic classification.

Final determination: Rule4 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 Pathogenic.

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	Met	NM_000051.4:c.7913G>A is a nonsense variant producing a premature termination codon at p.Trp2638 in exon 53 of ATM. Loss of function is a well-established disease mechanism for ATM, and the HBOP VCEP PVS1 decision tree supports application of PVS1 at very strong strength for this variant. The PTC is upstream of p.Arg3047 (the most C-terminal known pathogenic variant), and NMD is expected.	cspec pvs1_gene_context pvs1_variant_assessment vcep_atm_pvs1_1_5
PS1	N/A	PS1 applies to missense changes under the ATM VCEP. NM_000051.4:c.7913G>A is a nonsense variant, not a missense substitution.
PS2	N/A	Not applicable per the ATM HBOP VCEP v1.5: informative de novo occurrences have not been observed for ATM-related disorders, and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	No variant-specific experimental functional rescue data (ATM-specific kinase activity or radiosensitivity rescue) is available for c.7913G>A. The VCEP Suppl Table S1 (PMID:40580951) classifies this variant as Non-functional (High confidence) via computational prediction, but this is in silico evidence — the VCEP PS3 rule requires experimental rescue assay data (failure to rescue ATM-specific phosphorylation targets and/or radiosensitivity). Computational predictions do not independently satisfy the VCEP PS3 requirement.	vcep_suppl_tables1_pmid_40580951 cspec
PS4	Not met	No case-control study with p-value ≤0.05 and OR ≥2 (or lower 95% CI ≥1.5) is available for this variant. The ATM VCEP restricts PS4 to formal case-control studies meeting these statistical thresholds.	cspec
PS5	N/A	PS5 is not a defined criterion in the ATM HBOP VCEP v1.5 framework. The VCEP does not provide specifications for PS5; the semantics of same-residue pathogenic change for truncating variants are handled under PM5.	cspec
PM1	N/A	Not applicable per the ATM HBOP VCEP v1.5: benign and pathogenic variants are known to occur within the same domains, and germline mutational hotspots are not well defined for ATM at this time.	cspec
PM2	Met	c.7913G>A is present at extremely low frequency in gnomAD v4.1 (allele frequency = 0.00074%, 12/1,612,586 alleles, 0 homozygotes; grpmax FAF = 0.007%). This is well below the VCEP threshold of ≤0.001% for PM2_Supporting.	gnomad_v4 cspec
PM5	Met	c.7913G>A produces a premature termination codon at p.Trp2638, which is upstream of p.Arg3047 — the most C-terminal known pathogenic variant in ATM. PM5_Supporting applied per VCEP truncation cutoff rule for frameshifting or truncating variants with PTCs upstream of p.Arg3047.	cspec pm5_candidates
PM6	N/A	Not applicable per the ATM HBOP VCEP v1.5: informative de novo occurrences have not been observed for ATM-related disorders, and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	No co-segregation data in affected relatives is available for assessment. PP1 under the ATM VCEP requires documented segregation in AR-affected relatives carrying both variants identified in the proband.	cspec
PP2	N/A	Not applicable per the ATM HBOP VCEP v1.5: ATM does not have a defined low rate of benign missense variation.	cspec
PP3	Not met	PP3 under the ATM VCEP applies to missense variants with REVEL >0.7333 or splicing variants with SpliceAI ≥0.2. c.7913G>A is a nonsense variant with no REVEL score available, and SpliceAI max delta score is 0.15 (below the 0.2 threshold). The VCEP PP3 rule does not cover nonsense variants.	spliceai cspec
PP4	N/A	Not applicable per the ATM HBOP VCEP v1.5: for AD, breast cancer has multiple genetic etiologies with no distinguishing features from sporadic causes; for AR, phenotype evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	Not applicable per the ATM HBOP VCEP v1.5: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	gnomAD v4.1 grpmax filtering AF is 7.23e-05 (0.007%), well below the VCEP BA1 threshold of >0.5%.	gnomad_v4 cspec
BS1	Not met	gnomAD v4.1 grpmax filtering AF is 7.23e-05 (0.007%), well below the VCEP BS1 threshold of >0.05%.	gnomad_v4 cspec
BS2	N/A	Not applicable per the ATM HBOP VCEP v1.5: ATM has incomplete penetrance, precluding use of BS2.	cspec
BS3	Not met	No experimental evidence that c.7913G>A rescues ATM-specific function (kinase activity) or radiosensitivity. The VCEP BS3 rule requires rescue of both ATM-specific features and radiosensitivity (moderate) or either (supporting). The VCEP functional reference tables do not list this variant as having rescue data.	cspec
BS4	N/A	Not applicable per the ATM HBOP VCEP v1.5: informative lack of co-segregation in A-T families is too rare to be weighted, and co-segregation analysis in low-penetrance genes can yield false positives.	cspec
BP1	N/A	Not applicable per the ATM HBOP VCEP v1.5: missense pathogenic variants are known for ATM.	cspec
BP2	Not assessed	No proband data with trans observations in unaffected individuals is available to assign BP2 points per the ATM PM3/BP2 table.	cspec
BP4	Not met	BP4 under the ATM VCEP applies to missense variants with REVEL ≤0.249 or splicing variants with SpliceAI ≤0.1. c.7913G>A is a nonsense variant with no REVEL score, and SpliceAI max delta is 0.15 (above the 0.1 BP4 threshold). Neither condition is met.	spliceai cspec
BP5	N/A	Not applicable per the ATM HBOP VCEP v1.5: cases with multiple pathogenic variants have been observed with no noticeable phenotype difference, and ATM has low penetrance making co-occurrence with other pathogenic variants more frequent in the general population.	cspec
BP6	N/A	Not applicable per the ATM HBOP VCEP v1.5: this criterion 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 and deep intronic variants only. c.7913G>A is a nonsense variant.	cspec

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