Variant classification summary

NM_000051.4:c.7381C>T

ATM · NP_000042.3:p.(Arg2461Cys) · NM_000051.4

GRCh37: chr11:108201014 C>T · GRCh38: chr11:108330287 C>T

Gene: ATM Transcript: NM_000051.4

Final call

VUS

BP4 supporting

Variant details

Gene

ATM

Transcript

NM_000051.4

Protein

NP_000042.3:p.(Arg2461Cys)

gnomAD AF

6.133220994201318e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000051.4:c.7381C>T (p.Arg2461Cys) is a missense variant in ATM, a gene where loss of function is an established mechanism for Ataxia-Telangiectasia (AR) and heterozygous variants confer moderate risk for breast and other cancers (AD).

2

This variant is not a null variant and SpliceAI predicts no splicing impact (max delta 0.07); PVS1 is not applicable per the ATM VCEP v1.5.0 decision tree.

3

This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00613% (99/1,614,160 alleles; 0 homozygotes) with a grpmax filtering AF of 0.039%. The frequency exceeds the PM2_Supporting threshold (≤0.001%) but does not reach BS1 (>0.05%) or BA1 (>0.5%).

4

In silico predictions are inconclusive: REVEL score of 0.707 falls between the PP3 threshold (>0.7333) and BP4 missense threshold (≤0.249), neither meeting nor refuting pathogenicity. However, SpliceAI predicts no splicing impact (max delta 0.07 ≤ 0.1), satisfying BP4_Supporting.

5

This variant has been reported in ClinVar (VCV000142541) with predominantly uncertain significance classifications (14 clinical laboratories), with a minority of likely benign (3) and benign (1) submissions. No expert panel classification is available.

6

Functional evidence from the VCEP-validated Barone 2009 (PMID:19431188) kinase assay suggests partial impairment of ATM autophosphorylation, potentially supporting PS3_Supporting, but full-text verification of the variant-specific result was not possible in this assessment. Human review is recommended.

7

No case-control study meeting PS4 criteria, no published segregation data for PP1, and no phased trans/cis data for PM3/BP2 were identified for this variant.

8

Applying the ATM VCEP v1.5.0 criteria combination rules (Richards et al. 2015), only BP4_Supporting is met with no pathogenic criteria satisfied. The variant is classified as a Variant of Uncertain Significance (VUS). If PS3_Supporting is confirmed upon human review of the functional data, the variant would remain VUS (1 pathogenic supporting + 1 benign supporting under Rule31).

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 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice sites) per the ATM VCEP PVS1 decision tree. NM_000051.4:c.7381C>T is a missense variant (p.Arg2461Cys) and SpliceAI predicts no splicing impact (max delta 0.07), so it is not eligible for PVS1.	spliceai vcep_atm_pvs1_1_5
PS1	N/A	PS1 requires the same amino acid change (Arg2461Cys) resulting from a different nucleotide change. At codon 2461 (CGC→TGC), only c.7381C>T produces p.Arg2461Cys; no alternative nucleotide substitution yields this same amino acid change. No prior P/LP variant with the identical amino acid change exists.	vcep_atm_ps1_1_5
PS2	N/A	ATM VCEP v1.5.0 specifies that PS2 is not applicable for AD or AR disease; 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	The ATM VCEP functional assay spreadsheet (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) validates Barone 2009 (PMID:19431188) and Mitui 2009 (PMID:18634022) kinase assays as approved for PS3_Supporting/BS3_Supporting. Exploratory evidence suggests p.Arg2461Cys was tested and showed partial reduction in ATM kinase activity, potentially qualifying for PS3_Supporting under VCEP rules (failure to rescue ATM-specific phosphorylation). However, full-text verification of the specific variant result was not possible — PMID:19431188 and PMID:18634022 full-text files were not available in the case publication set. Human review is needed to confirm variant-specific functional data before applying PS3.	vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4	Not met	ATM VCEP requires a case-control study with p≤0.05 and OR≥2 (or lower 95% CI≥1.5) for PS4_Strong. No published case-control study with statistically significant enrichment of c.7381C>T in affected individuals versus controls was identified. The variant has been observed in cancer cohorts (ClinVar submissions, sarcoma study PMID:27498913) but without formal case-control odds ratio calculation for this specific variant.	clinvar gnomad_v4
PS5	N/A	PS5 is not part of the ATM VCEP v1.5.0 criteria framework.	cspec
PM1	N/A	ATM VCEP specifies PM1 is not applicable: 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	ATM VCEP applies PM2_Supporting when frequency is ≤0.001% in gnomAD v4. The variant has a gnomAD v4.1 overall allele frequency of 0.00613% (99/1,614,160 alleles), which exceeds the 0.001% threshold. The highest subpopulation frequency is 0.052% in African/African American (39/75,046 alleles). Although rare, the frequency does not meet the VCEP-defined cutoff for PM2_Supporting.	gnomad_v4
PM5	N/A	ATM VCEP applies PM5_Supporting only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants where PVS1_VS(RNA) is applied. This is a missense variant (p.Arg2461Cys), and the VCEP 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.'	cspec
PM6	N/A	ATM VCEP v1.5.0 specifies PM6 is not applicable 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	ATM VCEP applies PP1 for AR condition (Ataxia-Telangiectasia) when co-segregation is observed in affected relatives carrying both variants. No published segregation data or co-segregation analysis was identified for c.7381C>T in A-T families.
PP2	N/A	ATM VCEP specifies PP2 is not applicable: ATM does not have a defined low rate of missense benign variation.	cspec
PP3	Not met	ATM VCEP applies PP3_Supporting for missense variants when REVEL >0.7333, or for splicing when SpliceAI ≥0.2. The REVEL score for this variant is 0.707, which falls below the 0.7333 threshold. SpliceAI max delta is 0.07, below the 0.2 threshold. Neither computational criterion is met.	revel spliceai
PP4	N/A	ATM VCEP specifies PP4 is not applicable. For AD: breast cancer is a disease with multiple genetic etiologies and no features distinguish hereditary from sporadic causes. For AR: such evidence is built into the PM3/BP2 table.	cspec
PP5	N/A	ATM VCEP specifies PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BA1	Not met	ATM VCEP applies BA1 Stand-Alone when grpmax filtering AF exceeds 0.5% in gnomAD v4. The grpmax FAF for this variant is 0.039% in gnomAD v4.1, well below the 0.5% threshold. This variant is too rare to qualify as a common polymorphism.	gnomad_v4
BS1	Not met	ATM VCEP applies BS1_Strong when grpmax filtering AF exceeds 0.05% in gnomAD v4. The grpmax FAF for this variant is 0.039% in gnomAD v4.1, below the 0.05% threshold. The variant frequency does not exceed the expected prevalence for ATM-related disorders.	gnomad_v4
BS2	N/A	ATM VCEP specifies BS2 is not applicable: ATM has incomplete penetrance.	cspec
BS3	Not met	ATM VCEP applies BS3 when a variant rescues ATM-specific functional features. BS3_Moderate requires rescue of both an ATM-specific feature (e.g., phosphorylation of ATM-specific targets) AND radiosensitivity; BS3_Supporting requires rescue of either. Available evidence from exploratory search suggests p.Arg2461Cys impairs rather than rescues ATM kinase activity. No study demonstrates normal ATM function for this variant. BS3 is not met.
BS4	N/A	ATM VCEP specifies BS4 is not applicable. For AD: co-segregation analysis in low penetrance genes can lead to false positive results. For AR: informative instances of lack of co-segregation in A-T families are too rare to be considered.	cspec
BP1	N/A	ATM VCEP specifies BP1 is not applicable: missense pathogenic variants are known for ATM.	cspec
BP2	Not met	ATM VCEP applies BP2 when a variant is observed in cis with a pathogenic variant for A-T (recessive) or homozygous/trans in an unaffected individual ≥18 years with no evidence of A-T. No phased genotype data demonstrating cis configuration with a known pathogenic ATM variant, and no homozygous or confirmed trans observations in unaffected adults, were identified for c.7381C>T.
BP4	Met	ATM VCEP applies BP4_Supporting when SpliceAI predicts no splicing impact (max delta ≤0.1). SpliceAI predicts no significant splice impact for c.7381C>T (max delta score = 0.07), meeting the VCEP BP4 threshold for absence of predicted splicing disruption. The REVEL score of 0.707 does not meet the missense BP4 threshold (≤0.249), but BP4 is independently satisfied by the splicing computational evidence.	spliceai revel cspec
BP5	N/A	ATM VCEP specifies BP5 is not applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance resulting in more frequent co-occurrence with other pathogenic variants.	cspec
BP6	N/A	ATM VCEP specifies BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	ATM VCEP applies BP7 to synonymous and deep intronic variants (further than +7 at donor and -21 at acceptor). c.7381C>T is a missense variant (p.Arg2461Cys), not synonymous. BP7 is not applicable to missense variants.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.