NM_000051.4:c.4574T>C

ATM · NP_000042.3:p.(Ile1525Thr) · NM_000051.4

GRCh37: chr11:108163483 T>C · GRCh38: chr11:108292756 T>C

Gene: ATM Transcript: NM_000051.4

Final call

VUS

BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Ile1525Thr)

gnomAD AF

6.1953415987450715e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000051.4:c.4574T>C (p.Ile1525Thr) is a rare missense variant in ATM, present at extremely low frequency in gnomAD v4.1 (10/1,614,116 alleles; grpmax FAF = 1.425×10⁻⁵).

This variant has been reported in ClinVar as Uncertain Significance by 5 clinical laboratories (ClinVar ID 230535); no expert panel submission is available.

The VCEP HBOP v1.5.0 PVS1 criterion is not applicable because this is a missense variant, not a null variant.

Multiple lines of in silico evidence support a benign impact: REVEL score 0.116 is below the VCEP BP4 threshold (≤0.249), SpliceAI predicts no splice impact (max delta 0.06), and BayesDel score is −0.336. BP4 (supporting benign) is met.

No variant-specific functional studies, case-control data, segregation data, or pathogenic comparator at the same residue were identified in the literature. All other applicable VCEP criteria are not met.

Based on the VCEP HBOP v1.5.0 framework, the only criterion met is BP4_Supporting (benign). No pathogenic criteria are met. With only one supporting benign criterion and no conflicting evidence, the variant does not reach a classification threshold under the ACMG/AMP combining rules and remains a Variant of Uncertain Significance.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.5.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	NM_000051.4:c.4574T>C is a missense variant (p.Ile1525Thr). The VCEP PVS1 decision tree applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites). This variant does not fall into any PVS1 bucket.	pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No known pathogenic missense variant has been established at codon 1525 of ATM. Per the VCEP HBOP v1.5.0 PS1 rule, this criterion requires a previously established pathogenic variant at the same amino acid residue, with splicing ruled out for both variants. The ClinVar classification for this variant is Uncertain Significance; no pathogenic comparator at Ile1525 exists.	clinvar vcep_atm_ps1_1_5
PS2	N/A	The VCEP HBOP v1.5.0 specifies PS2 is not applicable for ATM: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	No variant-specific experimental functional data exists for p.Ile1525Thr. The VCEP HBOP v1.5.0 requires demonstration that the variant fails to rescue an ATM-specific feature (e.g. phosphorylation of ATM-specific targets) for PS3_Supporting, or both an ATM-specific feature and radiosensitivity for PS3_Moderate. The VCEP functional classification table (Suppl_TableS1) classifies c.4574T>C as 'Functional' based on in silico prediction, not experimental evidence. No functional study of this variant was identified in the literature.	cspec vcep_suppl_tables1_pmid_40580951
PS4	Not met	The VCEP HBOP v1.5.0 requires case-control studies demonstrating a statistically significant increase in variant prevalence in affected individuals (p≤0.05 AND OR≥2 or lower 95% CI≥1.5). No such case-control study has been reported for c.4574T>C. The variant is observed at extremely low frequency in gnomAD (AF ~6.2×10⁻⁶) and is classified as Uncertain Significance in ClinVar.	clinvar gnomad_v4 cspec
PS5	Not met	No pathogenic missense variant has been established at codon 1525 of ATM. PS5 (generic ACMG) requires a different pathogenic missense change at the same residue, which is not available for p.Ile1525. The VCEP does not include a PS5 criterion.	clinvar vcep_suppl_tables1_pmid_40580951
PM1	N/A	The VCEP HBOP v1.5.0 specifies PM1 is not applicable for ATM: 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	Not met	The VCEP HBOP v1.5.0 requires gnomAD v4 grpmax filtering allele frequency ≤0.001% for PM2_Supporting. The observed grpmax FAF is 1.425×10⁻⁵ (0.001425%), which exceeds the VCEP threshold of 0.001%. Although the variant is very rare (10/1,614,116 alleles in gnomAD v4), it does not meet the strict VCEP cutoff, and it is observed in multiple sub-populations (not n=1 in a single sub-population).	gnomad_v4 cspec
PM5	N/A	The VCEP HBOP v1.5.0 PM5 rule applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with NMD-prone PTCs. Missense changes are explicitly excluded: 'Do not use for missense changes.' c.4574T>C is a missense variant (p.Ile1525Thr).	cspec pm5_candidates
PM6	N/A	The VCEP HBOP v1.5.0 specifies PM6 is not applicable for ATM: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PP1	Not met	The VCEP HBOP v1.5.0 requires segregation data in affected relatives for the autosomal recessive condition (Ataxia-Telangiectasia). No segregation data for c.4574T>C has been identified in the literature or provided with this case.	cspec
PP2	N/A	The VCEP HBOP v1.5.0 specifies PP2 is not applicable: ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	The VCEP HBOP v1.5.0 requires REVEL score >0.7333 for missense variants. The REVEL score for c.4574T>C is 0.116, well below the pathogenic prediction threshold. SpliceAI max delta score is 0.06, indicating no predicted splicing impact.	revel spliceai cspec
PP4	N/A	The VCEP HBOP v1.5.0 specifies PP4 is not applicable: breast cancer has multiple genetic etiologies (genetic heterogeneity), and for the autosomal recessive condition, such evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	The VCEP HBOP v1.5.0 specifies PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	The VCEP HBOP v1.5.0 requires grpmax filtering allele frequency >0.5% in gnomAD v4 for BA1 Stand-Alone. The observed grpmax FAF is 1.425×10⁻⁵ (0.001425%), far below the 0.5% threshold.	gnomad_v4 cspec
BS1	Not met	The VCEP HBOP v1.5.0 requires grpmax filtering allele frequency >0.05% in gnomAD v4 for BS1. The observed grpmax FAF is 1.425×10⁻⁵ (0.001425%), below the 0.05% threshold.	gnomad_v4 cspec
BS2	N/A	The VCEP HBOP v1.5.0 specifies BS2 is not applicable: ATM has incomplete penetrance.	cspec
BS3	Not met	The VCEP HBOP v1.5.0 requires experimental functional evidence that the variant rescues ATM-specific features (e.g. phosphorylation of ATM-specific targets) and/or radiosensitivity. No such experimental functional data exists for p.Ile1525Thr in the literature.	cspec
BS4	N/A	The VCEP HBOP v1.5.0 specifies BS4 is not applicable: lack of co-segregation in A-T families is too rare to be informative, and co-segregation analysis in low-penetrance genes can lead to false positives.	cspec
BP1	N/A	The VCEP HBOP v1.5.0 specifies BP1 is not applicable: missense pathogenic variants are known for ATM.	cspec
BP2	Not met	The VCEP HBOP v1.5.0 BP2 rule requires observation of the variant in trans with a pathogenic variant in an unaffected individual ≥18 years old, or homozygous in an unaffected individual, applying the PM3/BP2 point table. No such observations have been identified for c.4574T>C.	cspec vcep_atm_pm3_bp2_1_5
BP4	Met	The VCEP HBOP v1.5.0 BP4 rule for missense variants requires REVEL score ≤0.249. The REVEL score for c.4574T>C is 0.116, which is below the 0.249 threshold. Additionally, SpliceAI predicts no splicing impact (max delta = 0.06, ≤0.1). Multiple lines of in silico evidence suggest no damaging effect on the gene product.	revel spliceai bayesdel cspec
BP5	N/A	The VCEP HBOP v1.5.0 specifies BP5 is not applicable: cases with multiple pathogenic variants have been observed in breast cancer genes, and ATM has low penetrance with higher tolerance in the general population.	cspec
BP6	N/A	The VCEP HBOP v1.5.0 specifies BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	NM_000051.4:c.4574T>C is a missense variant (p.Ile1525Thr). The VCEP HBOP v1.5.0 BP7 rule applies only to synonymous and deep intronic variants. Missense variants are not eligible for BP7.	cspec
BP3	N/A	In-frame deletions/insertions in repetitive region without known function; not applicable to this missense substitution.
PM3	N/A	Trivially not applicable: no trans-phase or homozygous observations of this variant with a second pathogenic ATM allele in an Ataxia-Telangiectasia proband.
PM4	N/A	Protein length changes due to in-frame deletions/insertions or stop-loss; not applicable to this missense substitution.

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