0%
ATMc.7630-2A>CLikely pathogenic
Print report
Variant interpretation report

ATM c.7630-2A>C, p.?

NM_000051.4:c.7630-2A>C NP_000042.3:p.? Canonical splice · intron 51 View identifiers
Classification
Likely pathogenic

Variant description:

The ATM NM_000051.4:c.7630-2A>C (NP_000042.3:p.?) splicing variant has previously been reported in somatic cancers (COSMIC; COSV105124714, n = 1 time). This variant is predicted to disrupt normal RNA processing, resulting in either an aberrant protein product or nonsense-mediated RNA decay. Based on available guidelines, this variant is considered to be Likely Pathogenic.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ATM

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.

NCBI Gene ↗ OncoKB ↗
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.
01The reasoning

How it was classified

The recorded framework is ClinGen ATM VCEP v1.6. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Strong
PVS1 · strong

Met, strong: canonical splice disruption produces exon skipping and a documented frameshift, while the in-frame exon-loss component triggers the VCEP's HEAT-domain strong limit.

PM3Moderate
PM3 · moderate

Met at Moderate: one confident A-T homozygous proband contributes 2.0 PM3 points under the ATM VCEP table.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PVS1 strong plus PM3 moderate satisfy the ATM VCEP v1.6 Rule11 combination.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
17 / 1,613,150 alleles

gnomAD v4.1: 17 / 1,613,150 alleles. Recorded AF 1.05384e-05. Recorded homozygote count 0.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.907 maximum delta

Recorded SpliceAI maximum delta score: 0.907. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
31 reported laboratory submissions

27 Pathogenic · 2 Likely pathogenic · 2 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV105124714, n = 1 times).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.6, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 4 not met · 7 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at strong strength because this canonical ATM splice variant has observed aberrant splicing including a documented frameshifting transcript, while the VCEP limits the in-frame single-exon-loss component to strong.

PM4 and BP3 are not applicable under the ATM VCEP v1.6 criterion-specific rules.

Among the requested codon, residue, and domain criteria, PM1, PP2, and BP1 are explicitly not applicable under the ATM v1.6 CSPEC. PS1 cannot be assessed because the governing PS1 splicing table lacks a distinct matched reference variant, and PM5 cannot be assessed because the required PVS1(RNA) Very Strong gate is not established.

PS2 and PM6 are not applicable under the ATM VCEP's autosomal-recessive de novo rule; PP1 is not assessed because informative affected-relative segregation is unavailable; BS4 is not applicable under the VCEP's A-T lack-of-cosegregation rule.

PM3 is met at Moderate strength from one qualifying confident-phenotype homozygous A-T proband contributing 2.0 VCEP points.

BP2 is not assessed because no qualifying unaffected adult or cis observation is documented.

For this canonical acceptor -2 splice-site variant, PP3 and BP7 are outside their VCEP-defined scopes; BP4 is not met because SpliceAI predicts substantial splice impact (max delta 0.907 versus <=0.1).

Met · 2

PVS1 StrongVCEPMet, strong: canonical splice disruption produces exon skipping and a documented frameshift, while the in-frame exon-loss component triggers the VCEP's HEAT-domain strong limit. Details ▾Hide ▴
Reasoning

NM_000051.4:c.7630-2A>C is a canonical acceptor -2 splice variant in ATM. The case evidence identifies exon 52 as the affected coding exon; complete exon skipping removes 159 coding nucleotides in-frame, while published RNA analysis reports aberrant transcripts with exon 54 skipping and loss of the first 11 nucleotides of exon 54, the latter causing a frameshift and premature termination. The affected exon is not terminal, and the VCEP states that ATM exons are constitutive without major rescue isoforms. The observed splice defect therefore supports PVS1(RNA), but the in-frame single-exon-loss component is limited to strong under the VCEP's HEAT-repeat-domain rule for PVS1-eligible alterations predicted to escape NMD. The ATM PVS1 file was searched for c.7630-2A>C and p.?; no variant-specific pre-assigned entry was found.

VCEP rule
PVS1 Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease ... The HEAT repeat domain is considered important for protein function based on the appearance of many A-T affected individuals harboring a variant resulting in an in-frame, single exon loss in this domain ... PVS1-eligible alterations that are predicted to escape NMD, but that adversely affect the HEAT repeat domain can be granted PVS1_Strong. They are limited to strong due to a lack of known missense pathogenic alterations in this domain.
Evidence considered
  • pvs1_variant_assessment: NM_000051.4:c.7630-2A>C; canonical acceptor (-2); affected coding exon 52 of 63; exon length 159 nt; complete exon skipping is in-frame.
  • ATM_PVS1_1.6.pdf, Notes: the default ATM transcript has constitutive exons without major alternate splice isoforms that could rescue presumed loss-of-function events.
  • ATM_PVS1_1.6.pdf, Notes: PVS1-eligible alterations predicted to escape NMD that adversely affect the HEAT repeat domain can be granted PVS1_Strong and are limited to strong.
  • PMID:9887333, Table 1 and splice-site mutation discussion: c.7630-2A>C was associated with skipping of exon 54 in 60% of transcripts and skipping of the first 11 nucleotides of exon 54 in 40%; no ATM protein was detected in the homozygous case.
  • PMID:21833744, Results and Table 2, family 3: c.7630-2A>C caused loss of 11 bp at the 5′ end of exon 54, frameshift, premature termination, and predicted p.Leu2544Asn fsX22.
Still missing
  • ATM_PVS1_1.6.pdf was searched for c.7630-2A>C and p.?; no variant-specific pre-assigned entry was found.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗pvs1_variant_assessmentPMID:9887333 ↗PMID:21833744 ↗
PM3 ModerateVCEPMet at Moderate: one confident A-T homozygous proband contributes 2.0 PM3 points under the ATM VCEP table. Details ▾Hide ▴
Reasoning

The ATM PM3/BP2 VCEP table assigns 2.0 PM3 points for a confident-phenotype A-T proband with a homozygous variant, and PMID:9887333 reports c.7630-2A>C homozygously in affected patient Ac049 with severe A-T manifestations; this meets PM3 at Moderate strength. The same paper reports three additional heterozygous A-T patients, but those observations do not independently establish a qualifying pathogenic/likely pathogenic second allele. PMID:25374739 documents the variant inherited from the father and c.5692C>T from the mother in an affected child, confirming trans phase, but the available evidence does not establish the maternal variant as P/LP under the ATM VCEP. PMID:21833744 reports compound heterozygosity with c.3848T>C, but the available evidence likewise does not establish that partner as P/LP under the ATM VCEP; these observations were therefore not added to the point total.

VCEP rule
PM3 = **2** points See ATM PM3/BP2 table for approach to assign points per proband.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, Ataxia Telangiectasia PM3 table: confident phenotype with a homozygous variant = 2.0 points; PM3 = 2 points corresponds to Moderate strength.
  • Characterization of ATM gene mutations in 66 ataxia telangiectasia families, Table 1 and Results: c.7630-2A>C was homozygous in patient Ac049, who had severe A-T manifestations; the variant caused exon 54 skipping in 60% of transcripts and loss of the first 11 exon nucleotides in 40%.
  • A precocious cerebellar ataxia and frequent Fever episodes in a 16-month-old infant revealing ataxia-telangiectasia syndrome, Case Report: c.7630-2A>C was inherited from the father and c.5692C>T from the mother in an affected child, establishing trans phase, but the available extraction does not establish c.5692C>T as VCEP P/LP.
  • Characterisation of ATM mutations in Slavic Ataxia telangiectasia patients, Family 3: c.7630-2A>C was reported in compound heterozygosity with c.3848T>C (p.Leu1283Pro), but the available extraction does not establish c.3848T>C as VCEP P/LP.
Still missing
  • No variant-specific entry for c.7630-2A>C, p.?, or p.? was found in ATM_PM3_BP2_1.6.pdf.txt; the assessment used its governing table and the case reports.
  • The available evidence does not provide VCEP-based P/LP classifications for the partner variants c.5692C>T or c.3848T>C, so the two phase-confirmed/compound-heterozygous observations were not credited as confirmed-in-trans PM3 points.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗PMID:9887333 ↗PMID:25374739 ↗PMID:21833744 ↗

Not met · 4 · evaluated, threshold not reached

PM2 VCEPNot met: the highest gnomAD v4.1 subpopulation AF is 0.00144145%, above the VCEP PM2 threshold of <=0.001%, with 17 observed alleles. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PM2 at Supporting when frequency is <=0.001% in the gnomAD subpopulation with the highest frequency, with an exception only when frequency is >0.001% but n=1 in a single subpopulation and absent from every other subpopulation. The default all-comers gnomAD v4.1 record is applicable because the VCEP rule does not specify a non-cancer or exome-only source. The highest subpopulation frequency is 1.44145e-05 (0.00144145%) in European (non-Finnish), based on 17 alleles, so it exceeds the threshold and does not meet the n=1 exception; PM2 is not met.

VCEP rule
Frequency <=.001% in gnomAD subpopulation with the highest frequency ... Exception: If >0.001% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2_supporting would apply.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC PM2 rule: Frequency <=.001% in gnomAD subpopulation with the highest frequency; exception applies only if >.001% but n=1 in a single subpopulation and not present in any other subpopulation.
  • gnomAD v4.1 all-comers record for NM_000051.4:c.7630-2A>C: highest subpopulation is European (non-Finnish), AF=1.44145e-05 (0.00144145%), AC=17, AN=1,179,372, homozygotes=0.
Sources
cspec ↗gnomad_v4 ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax FAF is 8.78e-06 (0.000878%), below the VCEP BA1 threshold of >0.5%. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BA1 as Grpmax Filtering AF >0.5% in gnomAD. The default all-comers gnomAD v4.1 record is the applicable population source because the VCEP rule does not specify a non-cancer or exome-only source; its grpmax FAF is 8.78e-06 (0.000878%), far below 0.5%, so BA1 is not met.

VCEP rule
Grpmax Filtering AF >.5% in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC BA1 rule: Grpmax Filtering AF >.5% in gnomAD.
  • gnomAD v4.1 all-comers record for NM_000051.4:c.7630-2A>C: grpmax FAF=8.78e-06 (0.000878%); total AF=1.05384e-05; 17/1,613,150 alleles; homozygotes=0; highest subpopulation AF=1.44145e-05 in European (non-Finnish).
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax FAF is 8.78e-06 (0.000878%), below the VCEP BS1 threshold of >0.05%. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BS1 as Grpmax Filtering AF >0.05% in gnomAD. The default all-comers gnomAD v4.1 record is the applicable population source because the VCEP rule does not specify a non-cancer or exome-only source; its grpmax FAF is 8.78e-06 (0.000878%), below 0.05%, so BS1 is not met.

VCEP rule
Grpmax Filtering AF >.05% in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC BS1 rule: Grpmax Filtering AF >.05% in gnomAD.
  • gnomAD v4.1 all-comers record for NM_000051.4:c.7630-2A>C: grpmax FAF=8.78e-06 (0.000878%); total AF=1.05384e-05; 17/1,613,150 alleles; homozygotes=0; highest subpopulation AF=1.44145e-05 in European (non-Finnish).
Sources
cspec ↗gnomad_v4 ↗
BP4 VCEPNot met: SpliceAI max delta 0.907 exceeds the VCEP BP4 no-predicted-impact cutoff of <=0.1. Details ▾Hide ▴
Reasoning

The VCEP BP4 splicing rule requires no predicted splice impact by SpliceAI <=0.1. The available SpliceAI max delta score is 0.907, with DS_AL 0.907 and DS_AG 0.535, which is inconsistent with the required no-impact threshold; therefore BP4 is not met.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • VCEP ATM v1.6 BP4 rule: splicing evidence requires no predicted impact via SpliceAI <=0.1.
  • SpliceAI Lookup for NM_000051.4:c.7630-2A>C reports max delta 0.907 (DS_AL 0.907; DS_AG 0.535; DS_DL 0.129; DS_DG 0.0).
  • Sun et al. 2025 Supplementary Table S1, exact row c.7630-2A>C: the governing table was searched and the row was found; its computational fields are not a pre-assigned BP4 code.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Not assessed · 7 · no assessment recorded

PS1 VCEPNot assessed: abnormal splicing is documented, but no distinct VCEP PS1 reference variant with a matched splice event and comparable prediction is available. Details ▾Hide ▴
Reasoning

The ATM v1.6 PS1 rule for splice variants requires use of the ATM PS1 Splicing table, with the same predicted splice event and comparable or stronger prediction than a distinct known pathogenic or likely pathogenic reference variant. The governing file ATM_PS1_1.6.pdf was searched for c.7630-2A>C and p.?; it contains the generic splice-event table but no variant-specific entry or distinct reference pairing for this variant. PMID:9887333 and PMID:21833744 document observed abnormal splicing of c.7630-2A>C, but they do not establish the required VCEP PS1 comparison to a different known pathogenic or likely pathogenic reference variant.

VCEP rule
Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. ... * Prerequisite for all: The predicted event of the VUA must precisely match the predicted event of the known (likely) pathogenic variant ... AND the strength of the prediction for the VUA must be of similar or higher strength than the strength of the prediction for the known (likely) pathogenic variant.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PS1 rule: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change"; for splicing, "Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect."
  • ATM_PS1_1.6.pdf generic splicing table: the prerequisite requires that the predicted event of the VUA precisely match the known pathogenic or likely pathogenic variant and that the VUA prediction be of similar or higher strength; no row for c.7630-2A>C or p.? was found.
  • PMID:9887333 reports c.7630-2A>C as an intron 53 splice-site mutation causing exon 54 skipping in 60% of transcripts and loss of the first 11 nucleotides of exon 54 in 40% of transcripts.
  • PMID:21833744 reports c.7630-2A>C causing loss of 11 bp at the 5' end of exon 54, frameshift, and premature termination, but does not provide the required distinct VCEP reference comparison.
Still missing
  • ATM_PS1_1.6.pdf was searched for c.7630-2A>C and p.?; no variant-specific entry or distinct reference pairing was found.
  • A distinct known pathogenic or likely pathogenic reference variant with a precisely matched splice event and comparable or weaker prediction is not identified.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗PMID:9887333 ↗PMID:21833744 ↗
PS3 Not assessed: Table S1 reports Classification=NA, Confidence=NA, and DeepATM_predicted=NA, while available variant-specific evidence is RNA splice disruption rather than PS3-qualified rescue testing. Details ▾Hide ▴
Reasoning

The exact c.7630-2A>C row in Sun et al. 2025 Supplementary Table S1 is annotated as Classification=NA, Confidence=NA, and DeepATM_predicted=NA, so the table supplies neither a direct prime-editing non-functional result for PS3 nor a computational prediction eligible for PS3. The ClinGen HBOP approved-assay supplementary tables are methodology and calibration tables rather than per-variant results, and a search found no entry for c.7630-2A>C or p.? in that file. Variant-specific RNA studies report abnormal splicing, including exon 54 skipping and loss of 11 nucleotides, but the ATM VCEP directs RNA splice evidence to PVS1_Strength(RNA), not PS3; no qualifying ATM-specific feature-rescue result or approved kinase/radiosensitivity result for this variant was identified.

Evidence considered
  • Sun et al. 2025, Supplementary Table S1, row ATM c.7630-2A>C: hg38_pos 108331877, consequence Splice_AD, GnomAD_all_AF 1.053838762669e-05, ClinVar_classification Pathogenic, Classification NA, Confidence NA, DeepATM_predicted NA.
  • ClinGen HBOP ATM Supplementary Tables 1 and 2: the file describes approved assay methods and strength calibration, not per-variant results; searches for c.7630-2A>C and p.? returned no matching entry.
  • ATM VCEP v1.6 PS3 rule: RNA splice evidence is directed to PVS1_Strength(RNA), whereas PS3 requires a variant-specific failure to rescue an ATM-specific feature, with radiosensitivity-only evidence excluded.
  • ATM c.7630-2A>C is reported with abnormal RNA splicing in PMID:9887333 and PMID:21833744, but neither extracted paper finding reports the VCEP-approved PS3 protein feature-rescue assay for this variant.
Still missing
  • The exact variant has no PS3-eligible direct-assay classification in Suppl_TableS1_PMID 40580951.xlsx.
  • No c.7630-2A>C or p.? entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; a qualifying approved kinase-activity or combined kinase-activity/radiosensitivity result for this variant remains unavailable.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗PMID:9887333 ↗PMID:21833744 ↗
PS4 VCEPNot assessed: no case-control p-value or odds ratio, relative risk, hazard ratio, or lower 95% confidence interval is reported for this variant. Details ▾Hide ▴
Reasoning

The VCEP permits PS4 only from case-control studies meeting both p-value and effect-size requirements. The available evidence consists of individual case reports and an AT cohort describing this variant, but provides no case-control p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval for this variant. Therefore the VCEP PS4 rule cannot be evaluated.

VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥2 **or** lower 95% CI ≥1.5).
Evidence considered
  • PMID:9887333, Table 1 and Results: c.7630-2A>C was identified in four AT families and showed exon 54 skipping in 60% of transcripts and loss of the first 11 nucleotides of exon 54 in 40%; this is a case/cohort observation, not a case-control effect estimate.
  • PMID:21833744, Results and Table 2, Family 3: c.7630-2A>C was reported in one AT patient in compound heterozygous state and associated with loss of 11 bases at the 5′ end of exon 54; no case-control statistics were reported.
  • PMID:25374739, Abstract and Case Report: c.7630-2A>C was reported in a child with AT and a compatible phenotype; no case-control statistics were reported.
Still missing
  • A case-control study result for this variant with p-value and odds ratio, hazard ratio, or relative risk is unavailable.
  • The lower 95% confidence interval for the relevant effect estimate is unavailable.
Sources
cspec ↗PMID:9887333 ↗PMID:21833744 ↗PMID:25374739 ↗
PM5 VCEPNot assessed: an observed frameshift is reported, but the VCEP requires PVS1(RNA) Very Strong with high-quality RNA data, which is not established here. Details ▾Hide ▴
Reasoning

The ATM v1.6 PM5 rule for splice variants applies only to observed NMD-prone truncating variants that receive PVS1(RNA) at Very Strong with high-quality RNA data and have a premature termination codon upstream of p.Leu3048. PMID:21833744 reports an observed c.7630del11 frameshift and premature termination, while PMID:9887333 reports mixed splice products including exon 54 skipping; however, this group's evidence does not establish a PVS1(RNA) Very Strong assignment, so the VCEP PM5 gate cannot be evaluated.

VCEP rule
Splice Variants: Apply only to observed (not predicted) NMD-prone, truncating variants receiving PVS1(RNA) (must be at VeryStrong with high-quality RNA data) with premature termination codons upstream of p.Leu3048. This is not applicable for predicted splice impact without RNA data or PVS1(RNA) at reduced strength.
Evidence considered
  • ATM v1.6 CSPEC PM5 rule: splice variants require observed, not predicted, NMD-prone truncation receiving PVS1(RNA) at Very Strong with high-quality RNA data and a premature termination codon upstream of p.Leu3048; predicted splice impact without RNA data or reduced-strength PVS1(RNA) is excluded.
  • PMID:21833744 reports loss of 11 bp at the 5' end of exon 54 (c.7630del11), frameshift, and premature termination; the paper lists p.Leu2544Asn fsX22.
  • PMID:9887333 reports two aberrant transcripts: exon 54 skipping in 60% and skipping of the first 11 nucleotides of exon 54 in 40%; no uniform PVS1(RNA) Very Strong assignment is supplied.
Still missing
  • A VCEP-compliant PVS1(RNA) Very Strong assignment based on high-quality RNA data is not available.
  • The reported RNA outcomes include both exon 54 skipping and an 11-nucleotide exon loss, so the required NMD-prone truncating outcome is not uniformly established.
Sources
cspec ↗PMID:9887333 ↗PMID:21833744 ↗
PP1 VCEPNot assessed: no informative affected-relative segregation series confirms both proband ATM variants in affected relatives, so the VCEP PP1 requirement cannot be evaluated. Details ▾Hide ▴
Reasoning

PP1 is applicable to the autosomal-recessive ATM condition only when affected relatives have both variants identified in the proband. The available literature documents the variant in affected individuals and, in one report, parental phase, but does not provide an informative affected-relative segregation series in which both proband variants are identified in the affected relatives. PMID:9887333 describes unrelated AT patients and PMID:21833744 describes one patient from family 3; PMID:25374739 describes a single affected child with carrier parents. The criterion therefore cannot be evaluated from the available segregation data.

VCEP rule
AR Condition: Affected relatives must have both variants identified in proband.
Evidence considered
  • The ATM VCEP PP1 rule requires that, for the autosomal-recessive condition, affected relatives must have both variants identified in the proband.
  • PMID:25374739 reports one affected child with c.5692C>T/c.7630-2A>C and parental testing showing the mother carried c.5692C>T and the father carried c.7630-2A>C; it does not report affected relatives segregating both variants.
  • PMID:9887333 reports c.7630-2A>C in four AT families/patients with molecular and functional characterization, but does not provide an informative affected-relative segregation series for both proband variants.
  • PMID:21833744 reports c.7630-2A>C in one patient from family 3 in compound heterozygous state with c.3848T>C, without reported affected-relative segregation data.
  • PMID:30067863 reports c.7630-2A>C in a single pancreatic cancer patient and provides no variant-specific segregation analysis.
Still missing
  • Informative affected relatives with documented testing for both ATM variants identified in the proband are not reported.
Sources
cspec ↗PMID:25374739 ↗PMID:9887333 ↗PMID:21833744 ↗PMID:30067863 ↗
BS3 Not assessed: Table S1 reports Classification=NA, Confidence=NA, and DeepATM_predicted=NA, and no variant-specific benign rescue assay is available for BS3. Details ▾Hide ▴
Reasoning

The exact c.7630-2A>C row in Sun et al. 2025 Supplementary Table S1 is annotated as Classification=NA, Confidence=NA, and DeepATM_predicted=NA, so it provides no direct prime-editing functional result supporting BS3. The ClinGen HBOP approved-assay supplementary tables are methodology and calibration tables rather than per-variant results, and a search found no entry for c.7630-2A>C or p.? in that file. The available variant-specific RNA evidence demonstrates aberrant splicing rather than rescue of an ATM-specific feature or radiosensitivity, so it cannot establish the VCEP BS3 requirement for a benign functional result.

Evidence considered
  • Sun et al. 2025, Supplementary Table S1, row ATM c.7630-2A>C: hg38_pos 108331877, consequence Splice_AD, GnomAD_all_AF 1.053838762669e-05, ClinVar_classification Pathogenic, Classification NA, Confidence NA, DeepATM_predicted NA.
  • ClinGen HBOP ATM Supplementary Tables 1 and 2: the file describes approved assay methods and strength calibration, not per-variant results; searches for c.7630-2A>C and p.? returned no matching entry.
  • ATM VCEP v1.6 BS3 rule requires rescue of either an ATM-specific feature or radiosensitivity; the available variant-specific studies report aberrant splicing, not rescue.
  • PMID:9887333 reports exon 54 skipping and absence of ATM protein in a homozygous case; PMID:21833744 reports loss of 11 bases from exon 54 with frameshift and premature termination. These findings do not support a benign functional effect.
Still missing
  • The exact variant has no BS3-eligible direct-assay classification in Suppl_TableS1_PMID 40580951.xlsx.
  • No c.7630-2A>C or p.? entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; a qualifying benign ATM-specific feature or radiosensitivity rescue result remains unavailable.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗PMID:9887333 ↗PMID:21833744 ↗
BP2 VCEPNot assessed: no unaffected adult or qualifying cis observation is documented for the BP2 requirement. Details ▾Hide ▴
Reasoning

The ATM VCEP BP2 rule requires an observation in cis with a pathogenic variant or an unaffected adult with a homozygous or in-trans pathogenic/likely pathogenic ATM variant. The available case evidence contains affected A-T patients and does not document an unaffected adult, a qualifying cis observation, or a VCEP-classified pathogenic/likely pathogenic partner for an unaffected individual; BP2 therefore cannot be evaluated.

VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. • When assessing homozygous or in trans variants (with a likely pathogenic or pathogenic ATM variant) for possible downgrade in an unaffected individual, the individual should be 18 years or older with no evidence of A-T.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, BP2 rule and table: BP2 applies to an unaffected adult (>18 years) with the relevant homozygous or in-trans observation, or to an observation in cis with a pathogenic variant; no such observation is documented here.
Still missing
  • No variant-specific entry for c.7630-2A>C, p.?, or p.? was found in ATM_PM3_BP2_1.6.pdf.txt.
  • No qualifying unaffected adult observation or cis-with-pathogenic-variant observation is available.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPNot applicable: the ATM VCEP excludes PS2 for autosomal-recessive disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP excludes PS2 for both autosomal dominant and autosomal recessive disease because informative de novo occurrences have not been observed and de novo autosomal-recessive conditions are unlikely to be informed by phase. The available case report instead documents the variant in the father, but that observation does not alter the VCEP applicability decision.

VCEP rule
Do not use 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
Evidence considered
  • The ATM VCEP instruction for PS2 states that it must not be used for AD or AR disease because informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
  • PMID:25374739 reports parental testing in which the father carried ATM c.7630-2A>C; this is inherited paternal transmission, not a de novo occurrence.
Sources
cspec ↗PMID:25374739 ↗
PM1 VCEPNot applicable: the ATM v1.6 CSPEC explicitly marks PM1 as Not Applicable, and no extracted ATM domain table is provided. Details ▾Hide ▴
Reasoning

The ATM v1.6 CSPEC marks PM1 as Not Applicable. The case vcep_materials.json domain_tables object is empty, so there is no authoritative extracted ATM domain list that can override the VCEP criterion applicability.

VCEP rule
Not Applicable
Evidence considered
  • ATM v1.6 CSPEC PM1 entry: applicability is "Not Applicable".
  • vcep_materials.json domain_tables: {}.
Sources
cspec ↗
PM4 N/ANot applicable: the VCEP limits PM4 to stop-loss variants, while this variant is a canonical splice-site change with protein consequence p.?. Details ▾Hide ▴
Reasoning

PM4 is not applicable because the ATM VCEP restricts this criterion to stop-loss variants, whereas NM_000051.4:c.7630-2A>C is a canonical splice-site variant with protein consequence p.? rather than a stop-loss change.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • ATM VCEP v1.6 CSPEC PM4 entry: applicability is limited to stop-loss variants; the case variant is NM_000051.4:c.7630-2A>C with NP_000042.3:p.?
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP excludes PM6 for autosomal-recessive disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP excludes PM6 for both autosomal dominant and autosomal recessive disease because informative de novo occurrences have not been observed and de novo autosomal-recessive conditions are unlikely to be informed by phase. The available case report documents paternal inheritance rather than an unconfirmed de novo event.

VCEP rule
Do not use 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
Evidence considered
  • The ATM VCEP instruction for PM6 states that it must not be used for AD or AR disease because informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
  • PMID:25374739 reports that the father carried ATM c.7630-2A>C, so the reported occurrence is inherited rather than an unconfirmed de novo occurrence.
Sources
cspec ↗PMID:25374739 ↗
PP2 VCEPNot applicable: the ATM v1.6 CSPEC explicitly marks PP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM v1.6 CSPEC marks PP2 as Not Applicable.

VCEP rule
Not Applicable
Evidence considered
  • ATM v1.6 CSPEC PP2 entry: applicability is "Not Applicable".
Sources
cspec ↗
PP3 N/ANot applicable: c.7630-2A>C is the canonical acceptor -2 site, outside the VCEP PP3 splice rule despite SpliceAI max delta 0.907. Details ▾Hide ▴
Reasoning

The VCEP's PP3 splicing rule applies SpliceAI >=0.2 to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites. NM_000051.4:c.7630-2A>C is the canonical acceptor -2 site, so this criterion is outside its stated scope despite the available SpliceAI max delta score of 0.907.

VCEP rule
* Missense: REVEL **\>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • VCEP ATM v1.6 PP3 rule: splicing evidence is for predicted impact via SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
  • SpliceAI Lookup for NM_000051.4:c.7630-2A>C reports DS_AG 0.535, DS_AL 0.907, DS_DG 0.0, DS_DL 0.129, and max delta 0.907.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7630-2A>C: variant class Splice_AD; the row has no pre-assigned PP3/BP4 code and reports the table's other fields as NA or Pathogenic where populated.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for ATM cancer predisposition and directs ataxia-telangiectasia phenotype evidence into PM3/BP2 instead. Details ▾Hide ▴
Reasoning

The VCEP marks PP4 not applicable for both ATM-related cancer predisposition and ataxia-telangiectasia: breast cancer has multiple genetic etiologies without distinguishing features, and phenotype evidence for ataxia-telangiectasia is incorporated into the PM3/BP2 table rather than used as a separate PP4 code.

VCEP rule
Autosomal Dominant: do not use as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. ... Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3|BP2 table
Evidence considered
  • VCEP PP4 instructions: for autosomal dominant ATM-related cancer predisposition, breast cancer is genetically heterogeneous without readily distinguishing features; for autosomal recessive ataxia-telangiectasia, phenotype evidence is built into the PM3/BP2 table.
Sources
cspec ↗
PP5 VCEPNot applicable: the VCEP explicitly states that PP5 is not for use. Details ▾Hide ▴
Reasoning

The VCEP explicitly designates PP5 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • VCEP PP5 applicability: Not Applicable for this VCEP; instruction: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP explicitly marks BS2 Not Applicable, despite zero homozygotes in gnomAD v4.1. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS2 Not Applicable. Therefore the absence of homozygotes in gnomAD v4.1 (0 homozygotes among 1,613,150 alleles) does not permit assessment or application of BS2 under this governing specification.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC applicability entry for BS2: Not Applicable.
  • gnomAD v4.1 all-comers record: homozygotes=0; total AC=17 and total AN=1,613,150.
Sources
cspec ↗gnomad_v4 ↗
BS4 VCEPNot applicable: the ATM VCEP states that informative lack of cosegregation in ataxia-telangiectasia families is too rare to receive weight. Details ▾Hide ▴
Reasoning

The ATM VCEP does not assign weight to informative lack of cosegregation in ataxia-telangiectasia families because such instances are too rare; it also notes that biallelic unaffected patients may instead be considered under BP2. Therefore BS4 is not applicable even though the reviewed reports do not establish a BS4 observation.

VCEP rule
AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.
Evidence considered
  • The ATM VCEP BS4 instruction states that informative instances of lack of cosegregation in A-T families are too rare to be considered for weight at this time and may also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM v1.6 CSPEC explicitly marks BP1 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM v1.6 CSPEC marks BP1 as Not Applicable.

VCEP rule
Not Applicable
Evidence considered
  • ATM v1.6 CSPEC BP1 entry: applicability is "Not Applicable".
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP explicitly marks BP3 as not applicable, and this variant is a documented canonical splice-site change. Details ▾Hide ▴
Reasoning

BP3 is explicitly marked Not Applicable in the ATM VCEP v1.6 CSPEC. The variant is a canonical splice-site change with documented aberrant splicing, not an in-frame deletion or insertion in a repetitive region.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC BP3 entry: Applicability = Not Applicable.
  • PMID:9887333 and PMID:21833744 document aberrant splicing for c.7630-2A>C rather than an in-frame repeat-region indel.
Sources
cspec ↗PMID:9887333 ↗PMID:21833744 ↗
BP5 VCEPNot applicable: the VCEP instructs that BP5 should not be used for ATM because multiple pathogenic variants may coexist without a noticeable phenotype difference. Details ▾Hide ▴
Reasoning

The VCEP explicitly designates BP5 as not applicable and instructs that it should not be used because multiple pathogenic variants have been observed without a noticeable phenotype difference and ATM has low penetrance.

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). ... In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
  • VCEP BP5 instructions: Do not use; cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance.
Sources
cspec ↗
BP6 VCEPNot applicable: the VCEP explicitly states that BP6 is not for use. Details ▾Hide ▴
Reasoning

The VCEP explicitly designates BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • VCEP BP6 applicability: Not Applicable for this VCEP; instruction: This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: c.7630-2A>C is a canonical acceptor -2 splice-site substitution, not synonymous or deep intronic beyond -21. Details ▾Hide ▴
Reasoning

The VCEP BP7 scope is limited to synonymous and deep intronic variants farther than, but not including, +7 at donor sites and -21 at acceptor sites, with a separate RNA-observation path. c.7630-2A>C is a canonical acceptor -2 splice-site substitution, so it is outside BP7's variant-type and location scope. The reviewed RNA studies report aberrant splicing rather than a lack of aberrant RNA defect, but that evidence is not needed to establish the upstream not-applicable determination.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • VCEP ATM v1.6 BP7 rule: use BP7 for synonymous and deep intronic variants farther than (but not including) +7 at donor and -21 at acceptor sites; BP7(RNA) requires an observed lack of aberrant RNA defect.
  • Tavtigian et al. / PMID:9887333 paper extraction: c.7630-2A>C caused skipping of exon 54 in 60% of transcripts and skipping of the first 11 nucleotides of exon 54 in 40% of transcripts in B-lymphoblastoid cells.
  • Soukupova et al. / PMID:21833744 paper extraction: c.7630-2A>C caused loss of 11 bp at the 5-prime end of exon 54, with frameshift and premature termination.
Sources
cspec ↗PMID:9887333 ↗PMID:21833744 ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.7630-2A>C
Protein (HGVS p.)
NP_000042.3:p.?
GRCh38
chr11:108331877 A>C
GRCh37
chr11:108202604 A>C
Location and type
Intron 51 · canonical splice
ClinVar
127447, 1759901
COSMIC
COSV105124714

Gene diagram

Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.4. Select a row to find it on the plot.

ATMNM_000051.4
Fetching transcript structure from UCSC…
gnomAD v4.1 17 / 1,613,150 alleles AF 1.05e-05 · 0 homozygotes · FAF 8.78e-06
gnomAD v2.1 3 / 282,512 alleles AF 1.06e-05 · 0 homozygotes · FAF 2.93e-06
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.1e-05 · 17 / 1,613,150 alleles · 0 hom · FAF 8.8e-06
European (non-Finnish)17 / 1,179,372 1.4e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 1.1e-05 · 3 / 282,512 alleles · 0 hom · FAF 2.9e-06
European (non-Finnish)3 / 128,914 2.3e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +2 bp
0.907
SpliceAI acceptor gainat +13 bp
0.535
SpliceAI donor lossat +160 bp
0.129
SpliceAI donor gainat -72 bp
0.000
Pangolin splice lossmagnitude shown
-0.813
Pangolin splice gain
0.720

Other predictors

REVEL
Not available
BayesDel
0.176

How the predictions were used

BP4 VCEPNot met: SpliceAI max delta 0.907 exceeds the VCEP BP4 no-predicted-impact cutoff of <=0.1. Details ▾Hide ▴
Reasoning

The VCEP BP4 splicing rule requires no predicted splice impact by SpliceAI <=0.1. The available SpliceAI max delta score is 0.907, with DS_AL 0.907 and DS_AG 0.535, which is inconsistent with the required no-impact threshold; therefore BP4 is not met.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • VCEP ATM v1.6 BP4 rule: splicing evidence requires no predicted impact via SpliceAI <=0.1.
  • SpliceAI Lookup for NM_000051.4:c.7630-2A>C reports max delta 0.907 (DS_AL 0.907; DS_AG 0.535; DS_DL 0.129; DS_DG 0.0).
  • Sun et al. 2025 Supplementary Table S1, exact row c.7630-2A>C: the governing table was searched and the row was found; its computational fields are not a pre-assigned BP4 code.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP3 N/ANot applicable: c.7630-2A>C is the canonical acceptor -2 site, outside the VCEP PP3 splice rule despite SpliceAI max delta 0.907. Details ▾Hide ▴
Reasoning

The VCEP's PP3 splicing rule applies SpliceAI >=0.2 to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites. NM_000051.4:c.7630-2A>C is the canonical acceptor -2 site, so this criterion is outside its stated scope despite the available SpliceAI max delta score of 0.907.

VCEP rule
* Missense: REVEL **\>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • VCEP ATM v1.6 PP3 rule: splicing evidence is for predicted impact via SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
  • SpliceAI Lookup for NM_000051.4:c.7630-2A>C reports DS_AG 0.535, DS_AL 0.907, DS_DG 0.0, DS_DL 0.129, and max delta 0.907.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7630-2A>C: variant class Splice_AD; the row has no pre-assigned PP3/BP4 code and reports the table's other fields as NA or Pathogenic where populated.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 N/ANot applicable: c.7630-2A>C is a canonical acceptor -2 splice-site substitution, not synonymous or deep intronic beyond -21. Details ▾Hide ▴
Reasoning

The VCEP BP7 scope is limited to synonymous and deep intronic variants farther than, but not including, +7 at donor sites and -21 at acceptor sites, with a separate RNA-observation path. c.7630-2A>C is a canonical acceptor -2 splice-site substitution, so it is outside BP7's variant-type and location scope. The reviewed RNA studies report aberrant splicing rather than a lack of aberrant RNA defect, but that evidence is not needed to establish the upstream not-applicable determination.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • VCEP ATM v1.6 BP7 rule: use BP7 for synonymous and deep intronic variants farther than (but not including) +7 at donor and -21 at acceptor sites; BP7(RNA) requires an observed lack of aberrant RNA defect.
  • Tavtigian et al. / PMID:9887333 paper extraction: c.7630-2A>C caused skipping of exon 54 in 60% of transcripts and skipping of the first 11 nucleotides of exon 54 in 40% of transcripts in B-lymphoblastoid cells.
  • Soukupova et al. / PMID:21833744 paper extraction: c.7630-2A>C caused loss of 11 bp at the 5-prime end of exon 54, with frameshift and premature termination.
Sources
cspec ↗PMID:9887333 ↗PMID:21833744 ↗

Statement

In silico

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

8 paper records listed. 3 cited in the classification.

Cited in the classification

  • Characterisation of ATM mutations in Slavic Ataxia telangiectasia patients.
    Soukupova J et al. · 2011 Sep
    The paper reports ATM c.7630-2A>C in a compound-heterozygous patient and states that it causes loss of 11 bp at the 5′ end of exon 54, frameshift, and premature termination; the table gives the predicted protein effect p.Leu2544Asn fsX22.
    → PVS1 · strong → PM3 · moderate Names this variant
    PMID 21833744 ↗
    Source detail
    In one AT patient (family no. 3), the second ATM allele carried the c.7630-2A [ C splice-site mutation, which leads to the loss of 11 bp at the 50end of exon 54 (c.7630del11), frameshift of the reading frame and premature termination of translation.

    Location Results, discussion of family 3; Table 2, Family 3

    Context ATM mutation screening in 12 patients from 11 ataxia-telangiectasia families using sequencing of the coding region and intron boundaries; splice effects were assessed by sequencing RT-PCR products from cDNA when available.

  • A precocious cerebellar ataxia and frequent Fever episodes in a 16-month-old infant revealing ataxia-telangiectasia syndrome.
    Nespoli L et al. · 2013
    This case report describes a child with ataxia-telangiectasia who carried ATM c.7630-2A>C in trans with c.5692C>T; the variant was inherited from the father and was located in intron 53.
    → PVS1 · strong → PM3 · moderate Names this variant
    PMID 25374739 ↗
    Source detail
    The characterization of the ATM gene mutations revealed 2 specific mutations (c.5692C > T/c.7630-2A > C) compatible with AT diagnosis.

    Location Abstract; Case Report, molecular study paragraph

    Context Single-patient case report with DNA molecular testing and parental testing; the father carried c.7630-2A>C and the mother carried c.5692C>T.

  • Characterization of ATM gene mutations in 66 ataxia telangiectasia families.
    The paper explicitly reports ATM c.7630-2A>C, written as 7630–2A→C, as an intron 53 splice-site mutation identified in four ataxia-telangiectasia families. In B-lymphoblastoid cells, it caused exon 54 skipping in 60% of transcripts and skipping of the first 11 nucleotides of exon 54 in 40%; no ATM protein was detected in the homozygous case.
    → PVS1 · strong → PM3 · moderate Names this variant
    PMID 9887333 ↗
    Source detail
    Skipping of exon 54 (60%) and skipping of the first 11 nt of exon 54 (40%)

    Location Table 1; Results, splice-site mutation discussion; Tables 3 and 4

    Context Cohort of 66 unrelated German ataxia-telangiectasia patients; genomic PCR and bidirectional sequencing; RT-PCR analysis of ATM mRNA from B-lymphoblastoid cells; ATM protein immunoblotting.

Other recorded publications

  • Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.
    Teraoka SN et al. · 1999
    No paper-specific finding is recorded.
    PMID 10330348 ↗
  • Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.
    Li A et al. · 2000
    No paper-specific finding is recorded.
    PMID 10817650 ↗
  • 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.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma.
    The paper explicitly reports ATM c.7630-2A>C in a 67-year-old White patient with pancreatic ductal adenocarcinoma. It classified the variant as a clinically actionable pathogenic germline variant detected by both guideline-based testing and a multigene panel, but reported no variant-specific segregation analysis.
    Names this variant
    PMID 30067863 ↗
    Quoted passage
    1_432362 ATM c.7630-2A>C 67 White Yes Yes Yes

    Table 2, clinically actionable PGVs in PDAC-associated genes

  • Ataxia-telangiectasia: identification and detection of founder-effect mutations in the ATM gene in ethnic populations.
    No paper-specific finding is recorded.
    PMID 9443866 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 17 / 1,613,150 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.907 Open source ↗
ClinVar 27 Pathogenic · 2 Likely pathogenic · 2 pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD 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.

gnomAD 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.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

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)

In silico

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

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV105124714, n = 1 times).