Classification rationale

PM2PP3 BS3BP7 Likely Benign

ATM c.5937A>G synonymous · exon 40

Likely Benign: BS3 supporting reflects high-confidence functional data classifying c.5937A>G as Functional. Likely Benign: BP7 supporting applies because c.5937A>G is synonymous. Supporting evidence: PM2 reflects absence from available gnomAD datasets. Supporting evidence: PP3 reflects a SpliceAI maximum delta of 0.247.

PM2 + PP3 + BS3 + BP7 → Likely Benign

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 9 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 4

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at Supporting: variant absent from gnomAD v2.1/v4.1 and non-cancer subsets, satisfying ATM VCEP's ≤0.001% highest-subpopulation frequency rule.

ATM VCEP version 1.6 defines PM2 Supporting as frequency ≤0.001% in the gnomAD subpopulation with the highest frequency; it also permits the criterion when a variant is absent.The variant is reported absent from gnomAD v2.1 and gnomAD v4.1, and absent from the available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer datasets.The available population observations therefore support an allele frequency of 0 in these datasets, below the VCEP threshold.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

PP3 supporting Pathogenic

Met at supporting: SpliceAI maximum delta 0.247 meets the ATM VCEP PP3 threshold of >=0.2 for predicted splice impact.

ATM VCEP version 1.6 specifies PP3 supporting for silent variants with predicted splice impact by SpliceAI >=0.2.SpliceAI for NM_000051.4:c.5937A>G reports DS_AG 0.002, DS_AL 0.247, DS_DG 0.000, and DS_DL 0.157; the maximum delta is 0.247.The searched ATM VCEP file Suppl_TableS1_PMID 40580951.xlsx contains the exact c.5937A>G row but does not pre-assign PP3 or BP4 and has NA predictor fields for this synonymous row.

cspec ↗spliceai ↗

BS3 supporting review Benign

Met, Supporting: direct prime-editing data classify c.5937A>G as Functional with high confidence, but VCEP acceptance of this non-approved assay requires human review.

ATM VCEP BS3: use Moderate when a variant rescues both an ATM-specific feature and radiosensitivity, and Supporting when it rescues either an ATM-specific feature or radiosensitivity.Table S1 row 18967 for c.5937A>G / E1979E reports Variant_consequence=Synonymous, Combined_score=0.119400150926129, Classification=Functional, Confidence=High, and DeepATM_predicted=No.DeepATM_predicted=No indicates that the Table S1 classification is based on the underlying prime-editing saturation genome-editing measurement rather than a computational extrapolation.

cspec ↗

BP7 supporting Benign

Met at supporting: ATM VCEP v1.6 assigns BP7 supporting to synonymous variants, and this variant is c.5937A>G (p.Glu1979=).

ATM VCEP version 1.6 specifies BP7 supporting for synonymous variants and states that BP7 is not considered conflicting evidence against a body of evidence supporting a pathogenic splice defect.NM_000051.4:c.5937A>G is annotated as synonymous, producing NP_000042.3:p.(Glu1979=).No variant-specific RNA evidence demonstrating lack of an aberrant splice defect was present, so BP7(RNA) was not assigned at a stronger variable strength.

cspec ↗spliceai ↗

Assessed · not applied · 4 not met · 5 not assessed

Pathogenic

PS1 Not assessed: SpliceAI max delta 0.247 exceeds the 0.2 splice-impact threshold, but no matching pathogenic reference event was found for the VCEP PS1 comparison.

PS3 Not met: Table S1 classifies c.5937A>G as Functional with high confidence, not as a loss-of-function result qualifying for ATM PS3.

PS4 Not assessed: no variant-specific case-control study, p-value, odds ratio, relative risk, hazard ratio, or confidence interval is available.

PM3 Not assessed: no affected-proband, homozygous, second-allele, or phase observation was available to assign the VCEP's PM3 points.

PP1 Not assessed: no affected-relative segregation, parental testing, or meiosis count is documented for applying the ATM VCEP PP1 thresholds.

Benign

BA1 Not met: gnomAD v2.1 and v4.1 report the variant as absent, not a group maximum filtering allele frequency above 0.5%.

BS1 Not met: gnomAD v2.1 and v4.1 report the variant as absent, not a group maximum filtering allele frequency above 0.05%.

BP2 Not assessed: no unaffected adult co-occurrence with a pathogenic ATM allele or phase evidence was available to assign the VCEP's BP2 points.

BP4 Not met: SpliceAI maximum delta 0.247 exceeds the ATM VCEP BP4 no-impact threshold of <=0.1.

N/A · 15 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 1750598)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.25).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

PMID 40580951

PMID 40580951 ↗

Found

Structured finding pending for this record — see source link.

Applied to

→BS3 supporting

The direct Functional/High/No result supports retained function and is the basis for tentative BS3_Supporting, pending VCEP acceptance of the assay.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

24366402 ↗ Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force. CLINVAR

24418350 ↗ EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. CLINVAR

31429903 ↗ Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. CLINVAR

31479213 ↗ PMID 31479213 CLINVAR

34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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