Variant classification summary

NM_000051.4:c.7357C>T

ATM · NP_000042.3:p.(Arg2453Cys) · NM_000051.4

GRCh37: chr11:108200990 C>T · GRCh38: chr11:108330263 C>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

PM2 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg2453Cys)

gnomAD AF

1.61090458488228e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.7357C>T (p.Arg2453Cys) is a missense variant in ATM exon 50, observed at very low frequency in population databases (gnomAD v4.1: 26/1,614,000 alleles, AF = 0.00161%; gnomAD v2.1: 3/251,250 alleles, AF = 0.00119%).

2

The variant meets PM2_supporting per the ClinGen HBOP VCEP v1.5.0 fallback rule: although global gnomAD v4 frequency (0.00161%) exceeds the primary threshold of ≤0.001%, the variant is observed at n=1 in the East Asian subpopulation, which is sufficiently rare to warrant supporting-level evidence for pathogenicity.

3

No pathogenic or likely pathogenic missense comparator at p.Arg2453 has been established (PS1 not met). REVEL score of 0.457 does not meet the VCEP PP3 threshold (>0.7333) or the BP4 threshold (≤0.249). SpliceAI predicts no splicing impact (max delta = 0.00).

4

No variant-specific functional assay data (PS3/BS3) or segregation data (PP1) are available. The VCEP functional assay reference tables do not include this variant. The VCEP Suppl Table S1 (PMID 40580951) classifies the variant as 'Functional' with high confidence based on combined in silico scores, but computational predictions alone do not constitute experimental functional evidence sufficient for PS3.

5

The variant has been reported in ClinVar as Uncertain Significance by 11 clinical laboratories (ClinVar Variation ID: 230366). No expert panel classification has been assigned. No peer-reviewed publication was identified that directly mentions NM_000051.4:c.7357C>T.

6

The variant has been reported in COSMIC (COSV104592374, n=5) in somatic cancers, but this observation does not independently support germline pathogenicity classification under the HBOP VCEP framework.

7

Applying the ClinGen HBOP VCEP v1.5.0 final classification rules (Richards et al. 2015 combining criteria), only PM2_supporting is met, with no benign criteria met. This does not reach the threshold for Likely Pathogenic (requires ≥2 supporting + ≥1 moderate, or ≥3 moderate, etc.) nor Likely Benign (requires ≥2 supporting benign). The variant is classified as 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	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, single/multi-exon deletion). NM_000051.4:c.7357C>T is a missense variant (p.Arg2453Cys) and does not fall into any PVS1-eligible variant class per the ClinGen HBOP VCEP ATM PVS1 decision tree.	vcep_atm_pvs1_1_5 pvs1_variant_assessment
PS1	Not met	PS1 requires a known pathogenic missense variant at the same amino acid residue (p.Arg2453) with splicing ruled out for both. No pathogenic or likely pathogenic missense comparator at p.Arg2453 was identified in ClinVar, the VCEP supplementary tables, or the reviewed literature. Three alternate substitutions at p.Arg2453 (R2453S, R2453G) are listed in the VCEP Suppl Table S1 but none has an established pathogenic classification in ClinVar.	vcep_atm_ps1_1_5 vcep_suppl_tables1_pmid_40580951
PS2	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM: informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.	cspec
PS3	Not met	No variant-specific experimental functional assay data were identified for NM_000051.4:c.7357C>T. The VCEP functional assay reference tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) do not list this variant in either the ATM kinase activity or radiosensitivity assay summaries. The VCEP PS3/BS3 specifications require demonstration of failure to rescue ATM-specific features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity in a validated assay system. The VCEP Suppl Table S1 (PMID 40580951) classifies c.7357C>T as 'Functional' with high confidence based on combined in silico scores, but this is a computational prediction, not experimental functional evidence meeting the PS3 threshold.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
PS4	Not met	No case-control study data are available for NM_000051.4:c.7357C>T. The VCEP requires a case-control study with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5. No such study has reported on this specific variant. Large consortium studies (e.g., BCAC, PMID:33471991) and ATM-specific case-control efforts (e.g., PMID:21787400, PMID:28779002) did not include or report this variant.	gnomad_v4 PMID:21787400 PMID:28779002
PS5	N/A	PS5 is not included in the ONLY ASSESS list for this adjudication.
PM1	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0: benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time for ATM.	cspec
PM2	Met	PM2_supporting applies under the VCEP fallback rule: although the global gnomAD v4.1 allele frequency (0.00161%, 26/1,614,000 alleles) exceeds the primary threshold of ≤0.001%, the variant is observed at n=1 in a single subpopulation (East Asian, AC=1, AN=44,878), which meets the VCEP criterion that a single-allele subpopulation occurrence is sufficiently rare to warrant PM2_supporting.	gnomad_v4
PM5	N/A	The ClinGen HBOP VCEP v1.5.0 explicitly states: 'Do not use for missense changes: Multiple amino acid substitutions at the same residue can be pathogenic or benign and bioinformatic tools cannot yet confidently distinguish them.' NM_000051.4:c.7357C>T is a missense variant (p.Arg2453Cys). PM5 is restricted to frameshifting or truncating variants with PTCs upstream of p.Arg3047, and splice variants with PVS1_VS(RNA) applied.	cspec pm5_candidates
PM6	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM: 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	No segregation data are available for NM_000051.4:c.7357C>T. The VCEP requires co-segregation in affected relatives with ataxia-telangiectasia (AR condition): ≥3 affected relatives for strong, 2 for moderate, or 1 for supporting. No published or ClinVar-submitted segregation evidence was identified for this variant.
PP2	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM.	cspec
PP3	Not met	The VCEP missense PP3 threshold requires REVEL >0.7333. The REVEL score for NM_000051.4:c.7357C>T is 0.457, which does not meet this threshold. SpliceAI predicts no splicing impact (max delta = 0.00), so the splicing arm of PP3 also does not apply.	revel spliceai
PP4	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM: breast cancer is a disease with multiple genetic etiologies and there are no features that readily distinguish hereditary from sporadic causes. For AR disease, this evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM.	cspec
BA1	Not met	The VCEP BA1 threshold requires a grpmax filtering allele frequency >0.5% in gnomAD v4. The grpmax FAF for NM_000051.4:c.7357C>T is 1.376e-05 (0.001376%), which is well below the BA1 threshold.	gnomad_v4
BS1	Not met	The VCEP BS1 threshold requires a grpmax filtering allele frequency >0.05% in gnomAD v4. The grpmax FAF for NM_000051.4:c.7357C>T is 1.376e-05 (0.001376%), which is well below the BS1 threshold.	gnomad_v4
BS2	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM.	cspec
BS3	Not met	No variant-specific experimental functional assay data demonstrating a benign effect (rescue of ATM-specific features and/or radiosensitivity) were identified. The VCEP functional assay reference tables do not list c.7357C>T. The VCEP Suppl Table S1 classifies the variant as 'Functional' (i.e., predicted damaging), which is inconsistent with a BS3 argument.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 vcep_suppl_tables1_pmid_40580951
BS4	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM.	cspec
BP1	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM.	cspec
BP2	Not met	No evidence of co-occurrence in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual aged ≥18 years was identified. The VCEP PM3/BP2 points-based table requires confirmation of phase or homozygosity for scoring.
BP3	N/A	Skipped per adjudication instructions: trivially not_applicable.
BP4	Not met	The VCEP BP4 missense threshold requires REVEL ≤0.249. The REVEL score for NM_000051.4:c.7357C>T is 0.457, which exceeds this threshold. The splicing arm of BP4 (SpliceAI ≤0.1) is met (max delta = 0.00), but this sub-rule is specified for splicing/silent/intronic variants, not missense variants.	revel spliceai
BP5	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM.	cspec
BP6	N/A	Not applicable per ClinGen HBOP VCEP v1.5.0 for ATM: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 is applicable only to synonymous substitutions and deep intronic variants (further than +7 and -21 at donor and acceptor sites, respectively). NM_000051.4:c.7357C>T is a missense variant (p.Arg2453Cys) in exon 50 and does not meet the variant class criteria for BP7.	cspec

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