LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-07
Case ID: NM_000051.4_c.103C_A_20260807_131625
Framework: ACMG/AMP 2015
Variant classification summary

NM_000051.4:c.103C>A

ATM  · NP_000042.3:p.(Arg35=)  · NM_000051.4
GRCh37: chr11:108098533 C>A  ·  GRCh38: chr11:108227806 C>A
Gene: ATM Transcript: NM_000051.4
Final call
Likely Benign
BS1 strong benign BP4 supporting benign BP7 supporting benign
All criteria require review: For research and educational purposes only.
Variant details
Gene
ATM
Transcript
NM_000051.4
Protein
NP_000042.3:p.(Arg35=)
gnomAD AF
4.8339896403883555e-05 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_000051.4:c.103C>A (p.Arg35=) is a synonymous variant in exon 3 of ATM.
2
This variant is present in gnomAD v4.1 at an allele frequency of 0.00483% (78/1,613,574 alleles) with a grpmax filtering allele frequency of 0.0626% in the African/African American population, exceeding the VCEP ATM BS1 threshold of >0.05% (BS1_Strong).
3
SpliceAI predicts no splicing impact (max delta = 0.00), supporting a benign interpretation (BP4_Supporting).
4
The variant is a synonymous substitution deep within exon 3, located 82 bases from the donor site and 30 bases from the acceptor site, well outside splice consensus regions. No aberrant splicing is predicted (BP7_Supporting).
5
The VCEP ATM ClinGen HBOP Supplementary Table S1 (PMID 40580951) classifies this variant as Benign/Likely benign based on computational prediction, consistent with the criteria assessment.
6
Classification: Likely Benign per VCEP ATM Rule 18 (1 Strong benign + ≥1 Supporting benign). BS1_Strong, BP4_Supporting, and BP7_Supporting are met. No pathogenic criteria are met.
Final determination: Rule19 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 Likely Benign.
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 Synonymous variant (p.Arg35=) does not fall into PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice sites, initiation codon, or exon deletion). VCEP ATM PVS1 decision tree does not apply.
pvs1_variant_assessment pvs1_gene_context cspec
PS1 N/A VCEP ATM PS1 applies to missense changes with splicing ruled out, or splicing variants with comparable predictions. NM_000051.4:c.103C>A is a synonymous variant (p.Arg35=) with no amino acid change; no comparator missense or splicing variant to evaluate.
cspec vcep_atm_ps1_1_5
PS2 N/A VCEP ATM marks PS2 as Not Applicable.
cspec
PS3 Not met No experimental functional studies exist for NM_000051.4:c.103C>A. VCEP ATM PS3 requires functional rescue assay data (failed rescue of ATM-specific feature and/or radiosensitivity), which is absent for this variant. The VCEP Supplementary Table S1 categorizes this variant as 'Functional' based on 'Computational prediction' only, not experimental evidence.
cspec vcep_suppl_tables1_pmid_40580951
PS4 Not met No case-control studies identified for NM_000051.4:c.103C>A. VCEP ATM PS4 requires case-control studies with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5. No such studies were found.
cspec
PS5 N/A PS5 is not defined in the VCEP ATM framework. No applicable VCEP rule exists for this criterion.
cspec
PM1 N/A VCEP ATM marks PM1 as Not Applicable.
cspec
PM2 Not met VCEP ATM PM2 requires gnomAD v4 frequency ≤0.001%. Observed gnomAD v4.1 allele frequency is 4.83×10⁻⁵ (0.00483%; 78/1,613,574 alleles), which exceeds the 0.001% threshold. PM2 is not met.
gnomad_v4 cspec
PM5 N/A VCEP ATM PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and to splice variants with NMD-prone PTCs where PVS1_VS(RNA) is applied. NM_000051.4:c.103C>A is a synonymous variant and does not meet these criteria.
cspec pm5_candidates
PM6 N/A VCEP ATM marks PM6 as Not Applicable.
cspec
PP1 Not met No segregation data is available for NM_000051.4:c.103C>A. VCEP ATM PP1 requires segregation in affected relatives for autosomal recessive ataxia-telangiectasia. No family studies were identified.
cspec
PP2 N/A VCEP ATM marks PP2 as Not Applicable.
cspec
PP3 Not met VCEP ATM PP3 requires REVEL >0.733 for missense variants or SpliceAI ≥0.2 for splicing variants. NM_000051.4:c.103C>A is synonymous: no REVEL score available, and SpliceAI max delta is 0.00. Neither threshold is met.
spliceai cspec vcep_suppl_tables1_pmid_40580951
PP4 N/A VCEP ATM marks PP4 as Not Applicable.
cspec
PP5 N/A VCEP ATM marks PP5 as Not Applicable.
cspec
BA1 Not met VCEP ATM BA1 requires grpmax filtering allele frequency >0.5% in gnomAD v4. Observed grpmax FAF in gnomAD v4.1 is 0.00062571 (0.0626%), well below the 0.5% threshold. BA1 is not met.
gnomad_v4 cspec
BS1 Met VCEP ATM BS1 requires grpmax filtering allele frequency >0.05% in gnomAD v4. Observed grpmax FAF in gnomAD v4.1 is 0.00062571 (0.0626%), exceeding the 0.05% threshold. The variant is present in 78 of 1,613,574 alleles in gnomAD v4.1 with highest subpopulation frequency in African/African American (AF=0.0787%). BS1 is met at Strong strength.
gnomad_v4 cspec vcep_suppl_tables1_pmid_40580951
BS2 N/A VCEP ATM marks BS2 as Not Applicable.
cspec
BS3 Not met No experimental functional data demonstrating rescue of ATM-specific features or radiosensitivity exists for NM_000051.4:c.103C>A. VCEP ATM BS3 requires functional rescue assays. The VCEP Supplementary Table S1 classifies this variant as 'Functional' based on 'Computational prediction' only, which does not constitute experimental rescue evidence.
cspec vcep_suppl_tables1_pmid_40580951
BS4 N/A VCEP ATM marks BS4 as Not Applicable.
cspec
BP1 N/A VCEP ATM marks BP1 as Not Applicable.
cspec
BP2 Not met No evidence of co-occurrence in trans with a pathogenic variant in ATM. VCEP ATM BP2 requires observation of the variant in trans with a pathogenic/likely pathogenic variant in unaffected (non-A-T) individuals, with point-based scoring per the PM3/BP2 table. No such data is available.
cspec vcep_atm_pm3_bp2_1_5
BP4 Met VCEP ATM BP4 for splicing: no predicted impact via splicing (SpliceAI ≤0.1). SpliceAI max delta score is 0.00 for NM_000051.4:c.103C>A, indicating no predicted splicing alteration. The variant is deep within exon 3 (82 bases from donor site, 30 bases from acceptor site). BP4 is met at Supporting strength.
spliceai cspec
BP5 N/A VCEP ATM marks BP5 as Not Applicable.
cspec
BP6 N/A VCEP ATM marks BP6 as Not Applicable.
cspec
BP7 Met VCEP ATM BP7 applies to synonymous variants located further than +7 from the donor site and further than -21 from the acceptor site. NM_000051.4:c.103C>A is a synonymous variant (p.Arg35=) in exon 3 (c.73-185), positioned 82 bases upstream of the donor site and 30 bases downstream of the acceptor site, well outside the splice consensus regions. SpliceAI delta is 0.00, confirming no predicted splicing impact. BP7 is met at Supporting strength.
spliceai cspec
BP3 N/A Skipped per instruction: in-frame indels only; substitution variant.
PM3 N/A Skipped per instruction: not in assess list for this case.
PM4 N/A Skipped per instruction: non-repeat indels and stop-loss only.
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.