Final classification

Likely Pathogenic

PVS1PS3PM2

ATM

c.3077+1G>A

p.?

canonical_splice · exon 20i

Gene context NCBI Gene ↗ OncoKB ↗

ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.

This variant

As a loss-of-function change in ATM, a tumor-suppressor gene that coordinates DNA-double-strand-break repair, this variant is relevant to ATM-related cancer predisposition and autosomal-recessive ataxia-telangiectasia.

Transcript

NM_000051.4

HGVS · transcript:coding

NM_000051.4:c.3077+1G>A

GRCh38

chr11:108271407 G>A

GRCh37

chr11:108142134 G>A

Likely Pathogenic: ATM VCEP Rule12 is met by PVS1 strong plus PS3 and PM2 supporting.

Classification rationale

PVS1PS3PM2 Likely Pathogenic

ATM c.3077+1G>A canonical_splice · exon 20i

Likely Pathogenic: PVS1 strong reflects a canonical +1 splice disruption with an in-frame exon-20 skip and an intact protein remainder. Likely Pathogenic: PS3 supporting reflects a high-confidence direct prime-editing result showing the exact variant is non-functional. Likely Pathogenic: PM2 supporting reflects a gnomAD maximum subpopulation frequency below the ATM VCEP rarity threshold.

PVS1 + PS3 + PM2 → Likely Pathogenic

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 · 3 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 · 3

Strength Supporting Moderate Strong Very strong

PVS1 strong Pathogenic

Met, strong: canonical +1 splice disruption predicts an in-frame 156-nucleotide exon-20 skip, triggering the VCEP's intact-remainder/escape-from-NMD downgrade rule.

Variant assessment: NM_000051.4:c.3077+1G>A; NP_000042.3:p.?; canonical donor (+1) splice variant; internal coding exon 20 of 63; exon 20 spans c.2922_3077 and contains 156 coding nucleotides.Variant assessment: predicted exon-20 skipping removes 156 coding nucleotides, with 156 % 3 = 0 and preserved reading frame; cryptic splice-site use is not modeled.ATM_PVS1_1.6.pdf, page 1: canonical +/-1 or 2 splice sites are PVS1-eligible null variants when LOF is a known disease mechanism; the same page cautions about exon skipping that leaves the remainder of the protein intact.

cspec ↗vcep_atm_pvs1_1_6 ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

PS3 supporting Pathogenic

Met at Supporting: direct prime-editing row classifies c.3077+1G>A as Non-functional with High confidence and DeepATM_predicted=No.

Sun et al. 2025, Supplementary Table S1, row c.3077+1G>A: hg38 position 108271407, G>A, exon_20, Splice_AD, Classification=Non-functional, Confidence=High, DeepATM_predicted=No, Combined_score=-3.24742909184742, ClinVar_classification=Likely pathogenic.The VCEP file-specific policy states that DeepATM_predicted=No with High, Medium-high, or Medium confidence represents a direct prime-editing measurement and that Classification=Non-functional supports PS3_Supporting.The approved functional assay table describes ATM kinase-activity and radiosensitivity methodology and strength calibration, but its variant-specific validation/result fields list other variants and do not contain c.3077+1G>A or p.? for this case.

cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗

PM2 supporting Pathogenic

Met at Supporting: highest observed gnomAD subpopulation AF is 0.0000847%, below the VCEP PM2 threshold of <=0.001%.

CSPEC criteria entry PM2, Supporting rule: Frequency <=.001% in gnomAD subpopulation with the highest frequency; singleton exception also specified.gnomAD v4.1 all-comers entry for NM_000051.4:c.3077+1G>A: highest observed subpopulation AF 8.474834825469252e-07 (0.0000847483%) in European (non-Finnish) individuals, 1/1,179,964 alleles, homozygotes 0.gnomAD v2.1 all-comers exomes entry: total AF 0 (0/250,488 alleles), highest observed subpopulation AF 0, homozygotes 0.

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

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

Pathogenic

PS1 Not assessed: the governing ATM PS1 splicing table contains no c.3077+1G>A or p.? entry establishing a matching reference splice event.

PS4 Not assessed: the only case-control result was gene-level ATM data (OR=1.88, lower 95% CI=1.10), not an exact-variant estimate.

PM3 Not assessed: no qualifying affected-proband observation or phase-established pathogenic ATM variant in trans is available for PM3 point assignment.

PP1 Not assessed: no documented affected-relative segregation count or variant-specific parental testing is available to meet the PP1 thresholds.

Benign

BA1 Not met: highest observed gnomAD subpopulation AF is 8.47e-7, far below the VCEP BA1 threshold of >0.5%.

BS1 Not met: highest observed gnomAD subpopulation AF is 0.0000847%, below the VCEP BS1 threshold of >0.05%.

BS3 Not met: direct prime-editing measurement classifies c.3077+1G>A as Non-functional, not as rescuing an ATM-specific feature or radiosensitivity.

BP2 Not assessed: no qualifying unaffected-adult observation documents this variant in trans or cis with a pathogenic ATM variant for BP2.

BP4 Not met: SpliceAI max delta 0.992 exceeds the VCEP BP4 no-impact threshold of ≤0.1.

N/A · 16 PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19604e-07; MAF= 0.00006%, 1/1613934 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47483e-07; MAF= 0.00008%, 1/1179964 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250488 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16164 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,613,934
0 hom

European (non-Finnish)

1 / 1,179,964

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / 250,488
0 hom

Not observed in any ancestry group.

+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

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 pathogenic (4 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 220036)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.337185.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has previously been reported in somatic cancers (COSMIC; COSV109415800, n = 5 times).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

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. 8 further PMIDs triaged but not cited — see Sources & references.

Sun et al. 2025

PMID 40580951 ↗

Searched

c.3077+1G>ANP_000042.3:p.?

Found

Sun et al. Supplementary Table S1 contains the exact variant c.3077+1G>A in exon 20 and classifies it as a high-confidence non-functional splice variant from direct prime-editing assessment, with DeepATM_predicted=No.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 strong

The exact variant's direct non-functional splice-assay result corroborates the predicted loss-of-function consequence used alongside the VCEP PVS1 rule.

→PS3 supporting

The exact-row direct prime-editing result is Non-functional with High confidence and supports PS3_Supporting under the VCEP file-specific rule.

108271407 G A c.3077+1G>A exon_20 11 Splice_AD 35 NA NA NA NA 6.84133039247344e-07 Likely pathogenic -3.24742909184742 Non-functional High No

Location Supplementary Table S1, converted full-text row 9790 · Context Sun et al. 2025 functional assessment of ATM single-nucleotide variants using prime editing and deep learning; the exact row is marked Non-functional, High confidence, and DeepATM_predicted=No. · full text

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 8 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

32853339 ↗ Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer. CLINVAR

20301790 ↗ Ataxia-Telangiectasia. CLINVAR

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

24432435 ↗ PMID 24432435 CLINVAR

35220195 ↗ Evaluation of hereditary/familial breast cancer patients with multigene targeted next generation sequencing panel and MLPA analysis in Turkey. CLINVAR

35260754 ↗ Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India. CLINVAR

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