Final classification

VUS

PVS1PM3

ATM

c.7630-2A>C

p.?

canonical_splice · exon 51i

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

By disrupting ATM pre-mRNA splicing, this variant affects a tumor-suppressor gene whose loss of function contributes to ataxia-telangiectasia and cancer predisposition.

Transcript

NM_000051.4

HGVS · transcript:coding

NM_000051.4:c.7630-2A>C

GRCh38

chr11:108331877 A>C

GRCh37

chr11:108202604 A>C

VUS: PVS1 (very strong) and PM3 (very strong) are applied, but the ATM VCEP Version 1.6 has no satisfied combination rule for these criteria alone.

Classification rationale

PVS1PM3 VUS

ATM c.7630-2A>C canonical_splice · exon 51i

PVS1 very strong: the canonical splice-site variant causes aberrant ATM splicing and absent ATM protein. PM3 very strong: 10.0 aggregated affected A-T observations exceed the ATM VCEP threshold of 8 points.

PVS1 + PM3 → VUS

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 · 2 applied · 11 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 · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong review Pathogenic

Met, very strong: canonical -2 splice-site disruption caused aberrant transcripts and absent ATM protein, with no applicable VCEP downgrade rule.

NM_000051.4:c.7630-2A>C is annotated as a canonical splice acceptor (-2) variant with protein consequence NP_000042.3:p.?; the case-level assessment identifies affected exon 52 of 63, 159 coding nucleotides, and an in-frame exon-skipping prediction.ATM_PVS1_1.6.pdf governing text: the VCEP defines PVS1-eligible null variants to include canonical +/-1 or 2 splice sites and states that all exons of the default RefSeq transcript can be considered constitutive without major alternate splice isoforms that could rescue presumed loss-of-function events.PMID:10330348, Results and Table 2: exact variant IVS53-2A>C caused skipping of exon 54; the study used genomic sequencing, cDNA analysis, and ATM protein western blotting.

cspec ↗vcep_atm_pvs1_1_6 ↗PMID:10330348 ↗PMID:9887333 ↗

PM3 very strong review Pathogenic

Met, 10.0 aggregated PM3 points from one confirmed-in-trans A-T case plus additional affected-family observations exceeds the VCEP Very Strong threshold of 8 points.

ATM_PM3_BP2_1.6.pdf, Ataxia Telangiectasia PM3/BP2 table: confident A-T phenotype with confirmed in-trans pathogenic variant = 4.0 points; phase unknown = 2.0; second variant unidentified or VUS = 1.0; homozygous = 2.0; PM3 Very Strong requires at least 8 points.PMID:25374739, case report molecular-study paragraph: c.5692C>T/c.7630-2A>C, with the mother carrying c.5692C>T and the father carrying c.7630-2A>C; the reported child had A-T clinical and laboratory findings. Assigned 4.0 points for confident phenotype and confirmed trans phase.PMID:9887333, Table 1 and results: c.7630-2A>C was found in Aa002, Aa009, Aa051 as heterozygous samples and Ac049 as a homozygous sample; assigned 3.0 points for the three heterozygous observations with second variant/phase not established and 2.0 points for the homozygous observation.

cspec ↗vcep_atm_pm3_bp2_1_6 ↗PMID:25374739 ↗PMID:9887333 ↗PMID:10330348 ↗

Assessed · not applied · 4 not met · 7 not assessed

Pathogenic

PS1 Not assessed: observed exon-54 splicing defects are documented, but no separate known pathogenic reference variant with the same event is identified in the governing PS1 table.

PS3 Not assessed: the Sun Table S1 row has Confidence=NA and DeepATM_predicted=NA, while the VCEP routes observed RNA splice defects to PVS1_Strength(RNA), not PS3.

PS4 Not assessed: reported cases are available, but no qualifying case-control p-value and odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is reported.

PM2 Not met: the highest gnomAD subpopulation AF is 0.001441% (17 alleles), exceeding the VCEP's <=0.001% PM2 threshold and not qualifying for the n=1 exception.

PM5 Not assessed: RNA confirms aberrant splicing, but the required VCEP PVS1(RNA) Very Strong assignment and NMD-prone truncating eligibility are not established.

PP1 Not assessed: one affected child had paternal c.7630-2A>C, but no affected relative was documented for the VCEP's one-relative segregation threshold.

Benign

BA1 Not met: gnomAD grpmax filtering AF is 8.78e-06 (0.000878%), below the VCEP's >0.5% BA1 threshold.

BS1 Not met: gnomAD grpmax filtering AF is 8.78e-06 (0.000878%), below the VCEP's >0.05% BS1 threshold.

BS3 Not assessed: no qualifying benign rescue result exists, and the exact Table S1 row is Pathogenic with Confidence=NA and DeepATM_predicted=NA.

BP2 Not assessed: no qualifying unaffected adult observation with documented pathogenic-variant trans or cis phase is available for the VCEP BP2 table.

BP4 Not met: SpliceAI maximum delta 0.907 exceeds the VCEP BP4 no-impact threshold of ≤0.1.

N/A · 15 PS2 · PM1 · PM4 · PM6 · PP2 · PP3 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.05384e-05; MAF= 0.00105%, 17/1613150 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.44145e-05; MAF= 0.00144%, 17/1179372 alleles, homozygotes = 0); grpmax FAF= 8.78e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.0619e-05; MAF= 0.00106%, 3/282512 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.32713e-05; MAF= 0.00233%, 3/128914 alleles, homozygotes = 0); grpmax FAF= 2.93e-06.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0011% · 17 / 1,613,150
0 hom · FAF 0.00088%

European (non-Finnish)

17 / 1,179,372

0.0014%

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

gnomAD v2.1

0.0011% · 3 / 282,512
0 hom · FAF 0.00029%

European (non-Finnish)

3 / 128,914

0.0023%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (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 Pathogenic (27 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as pathogenic (2 clinical laboratories). (ClinVarID = 127447)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.91). BayesDel score = 0.176238.

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; COSV105124714, n = 1 times).

Hotspots

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

COSMIC ↗

Literature · how each cited paper was used

3papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.

Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.

PMID 10330348 ↗ · Teraoka SN et al. · 1999 Jun CLINVAR · functional

Searched

c.7630-2A>CNP_000042.3:p.?

Found

The paper explicitly reports the ATM intronic variant IVS53-2A>C in patient cell line AT72LA. Table 2 associates this variant with an ATM cDNA deletion designated 7630del159 and reports skipping of exon 54. The study identified this consequence through cDNA analysis and genomic sequencing; no variant-specific segregation or population-frequency data are reported in the supplied text.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 very strong

The exact canonical splice variant is experimentally shown to cause exon skipping, supporting a loss-of-function consequence.

→PM3 very strong

Documents the exact splice-site variant in an affected A-T patient cell line, supporting the affected-proband PM3 point assignment when phase is not established.

Two mutations, IVS9-1GrT (in AT134LA) and IVS53-2ArC (in AT72LA), resulted in skipping of exons 10 and 54, respectively (table 2).

Location Results, ‘Mutations in Canonical Splice Sites’; Table 2, AT72LA · Context ATM mutation study of 49 ataxia-telangiectasia patient cell lines; genomic DNA sequencing, cDNA SSCP/direct sequencing, and ATM protein western blotting. · full text

A precocious cerebellar ataxia and frequent Fever episodes in a 16-month-old infant revealing ataxia-telangiectasia syndrome.

PMID 25374739 ↗ · Nespoli L et al. · 2013 CLINVAR · functional

Searched

c.7630-2A>Cc.7630-2A > Cparentfathermothersegregation

Found

The paper reports ATM c.7630-2A>C in an affected child with ataxia-telangiectasia; the child inherited c.7630-2A>C from the father and c.5692C>T from the mother. This establishes parental phase but does not document segregation in an affected relative.

Variant

✓ Names this variant — characterised directly

Applied to

→PM3 very strong

Affected A-T case with parental evidence establishing the variant in trans with another ATM variant.

A blood sample was sent to the laboratory for the DNA molecular study of the ATM gene mutations which revealed 2 specific mutations (c.5692C > T/c.7630-2A > C) compatible with AT diagnosis (mother: c.5692C > T mutation; father: c.7630-2A > C on intron 53).

Location Case Report, paragraph describing the ATM molecular study · Context Single pediatric ataxia-telangiectasia case; ATM molecular genetic testing with parental origin reported; no additional affected-relative segregation analysis was described. · full text

Characterization of ATM gene mutations in 66 ataxia telangiectasia families.

PMID 9887333 ↗ CLINVAR · splicing rna

Searched

c.7630-2A>C7630–2A→CNP_000042.3:p.?

Found

The paper explicitly identifies ATM c.7630-2A>C as a splice-site mutation in intron 53, found in four AT families: three heterozygous samples (Aa002, Aa009, Aa051) and one homozygous sample (Ac049). RT-PCR analysis of B-lymphoblastoid cell lines showed two aberrant ATM transcripts: skipping of exon 54 in 60% of transcripts and use of a cryptic acceptor causing skipping of the first 11 nucleotides of exon 54 in 40%. In the homozygous cell line, no ATM protein was detected by immunoblotting. The paper also states that this mutation had been independently reported in Polish patients.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 very strong

The exact variant has observed aberrant splicing, cryptic acceptor use, and absent ATM protein in a homozygous cell line.

→PM3 very strong

Provides multiple A-T observations with heterozygous and homozygous zygosity information used in the VCEP PM3 points table.

7630–2A→C | Intron 53 | Aberrant splicing | Aa002 (het) Aa009 (het) Aa051 (het) Ac049 (hom)

Location Table 1; Results, splice-site mutation paragraph; Table 3; Table 4; final Results paragraph · Context Cohort of 66 unrelated German ataxia-telangiectasia patients; genomic exon and flanking-intron sequencing; RT-PCR analysis of ATM mRNA from B-lymphoblastoid cell lines; ATM immunoblotting in cell lines. · full text

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 5 PMIDs not cited in assessment

10817650 ↗ Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients. CLINVAR

21833744 ↗ Characterisation of ATM mutations in Slavic Ataxia telangiectasia patients. CLINVAR

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

30067863 ↗ Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma. CLINVAR

9443866 ↗ Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations. CLINVAR

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