About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.7875_7876delinsGC, p.(Asp2625_Ala2626delinsGluPro)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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 v1.5.0. 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
PS3Supporting
PS3 · supporting
Functional studies demonstrate that this variant abrogates ATM kinase activity, an ATM-specific feature. In a genotype-phenotype study of 51 A-T patients (PMID:22213089), nine patients (13 alleles) carried c.7875_7876delTGinsGC; those homozygous were classified as Group 2 (ATM protein present but without detectable kinase activity), as shown by absent phosphorylation of ATM-specific downstream targets (SMC1, KAP-1, CREB). In a separate study (PMID:10873394), a homozygous patient (AT152LA) had no detectable ATM protein by Western blot. Per VCEP PS3_Supporting: variant fails to rescue an ATM-specific feature (phosphorylation of ATM targets). Radiosensitivity was not independently demonstrated for this variant to meet PS3_Moderate.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0. The allele frequency of 0.0% is ≤0.001%, meeting the ATM VCEP PM2_Supporting threshold.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PS3 supporting, PM2 supporting; no rule matched the adjudicated criteria.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.120 maximum delta
Recorded SpliceAI maximum delta score: 0.120. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
13 reported laboratory submissions
9 Pathogenic · 4 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 10 not met · 0 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000051.4:c.7875_7876delinsGC (p.Asp2625_Ala2626delinsGluPro) is an in-frame deletion-insertion in exon 55 of ATM. PVS1 does not apply as this is not a null variant type per ATM VCEP definition.
Functional studies demonstrate that this variant abrogates ATM kinase activity. In a genotype-phenotype study of 51 A-T patients (PMID:22213089), homozygous individuals showed ATM protein present but without detectable kinase activity (Group 2), failing to phosphorylate ATM-specific downstream targets including SMC1, KAP-1, and CREB. A separate study (PMID:10873394) found no detectable ATM protein by Western blot in a homozygous patient (AT152LA). Per ATM VCEP, PS3_Supporting applies: variant fails to rescue an ATM-specific feature (phosphorylation of targets).
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the ATM VCEP PM2_Supporting threshold (frequency ≤0.001%).
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and Likely Pathogenic (4 laboratories) (ClinVar Variation ID: 3030). While many submitters cite supporting literature, the ClinVar classification is not independently weighted under VCEP criteria.
No benign criteria were met. The available evidence yields PS3_Supporting and PM2_Supporting, totaling two pathogenic supporting criteria.
No criteria match.
Met · 2
PS3 SupportingFunctional studies demonstrate that this variant abrogates ATM kinase activity, an ATM-specific feature. In a genotype-phenotype study of 51 A-T patients (PMID:22213089), nine patients (13 alleles) carried c.7875_7876delTGinsGC; those homozygous were classified as Group 2 (ATM protein present but without detectable kinase activity), as shown by absent phosphorylation of ATM-specific downstream targets (SMC1, KAP-1, CREB). In a separate study (PMID:10873394), a homozygous patient (AT152LA) had no detectable ATM protein by Western blot. Per VCEP PS3_Supporting: variant fails to rescue an ATM-specific feature (phosphorylation of ATM targets). Radiosensitivity was not independently demonstrated for this variant to meet PS3_Moderate. Details ▾Hide ▴
Evidence considered
- Loss of ATM kinase activity in homozygous state (PMID:22213089
- Group 2 patients)
- Absence of detectable ATM protein in homozygous patient AT152LA (PMID:10873394)
Still missing
- Radiosensitivity data not available specifically for this variant
- PS3_Moderate cannot be applied without radiosensitivity evidence
Sources
PM2 SupportingThis variant is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0. The allele frequency of 0.0% is ≤0.001%, meeting the ATM VCEP PM2_Supporting threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (grpmax FAF = null)
- Absent from gnomAD v2.1
- Absent from gnomAD-Canada v1.0
Sources
Not met · 10 · evaluated, threshold not reached
PVS1 This variant is an in-frame deletion-insertion (c.7875_7876delinsGC, p.Asp2625_Ala2626delinsGluPro) and does not meet the ATM VCEP PVS1 definition of a null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion). PVS1 is reserved for variants predicted to result in absent protein via NMD or truncation. Details ▾Hide ▴
Evidence considered
- In-frame 2 bp deletion and 2 bp insertion
- net effect is substitution of two amino acids (Asp2625_Ala2626→GluPro). No PTC
- no frameshift
- no NMD predicted.
PS4 No case-control study meeting ATM VCEP PS4 criteria (p-value ≤0.05 AND odds ratio/relative risk ≥2 OR lower 95% CI ≥1.5) was identified for this variant. A Norwegian breast cancer screening study (PMID:11104561) included this variant in a mutation panel but detected no carriers among 483 patients. Details ▾Hide ▴
Evidence considered
- Zero carriers of this variant detected among 483 breast cancer patients (PMID:11104561)
Still missing
- No case-control study specific to this variant available
Sources
PM4 ATM VCEP PM4 is reserved for stop-loss variants. This variant is an in-frame deletion-insertion and does not create a stop-loss. Details ▾Hide ▴
Evidence considered
- Not a stop-loss variant
PP1 No segregation data available. ATM VCEP PP1 requires segregation analysis in AR condition (AT): ≥3 affected relatives for Strong, 2 for Moderate, 1 for Supporting. No published data on co-segregation of c.7875_7876delinsGC with disease in multiple affected relatives were identified. Details ▾Hide ▴
Still missing
- No segregation studies available
PP3 SpliceAI max delta score for this variant is 0.12, below the ATM VCEP PP3 threshold of ≥0.2 for splicing variants. REVEL score is not available as this is not a missense variant. Neither in-silico criterion threshold is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.12 (<0.2 VCEP threshold)
- REVEL not available for in-frame indel
Sources
BA1 Variant is absent from gnomAD v4.1. Grpmax filtering allele frequency is not >0.5%. Does not meet the ATM VCEP BA1 threshold. Details ▾Hide ▴
BS1 Variant is absent from gnomAD v4.1. Grpmax filtering allele frequency is not >0.05%. Does not meet the ATM VCEP BS1 threshold. Details ▾Hide ▴
BS3 Functional evidence demonstrates loss of ATM function (absent kinase activity, absent protein), not rescue. ATM VCEP BS3 requires evidence that the variant rescues ATM-specific features and/or radiosensitivity. The available functional data show the opposite: abrogation of ATM kinase activity in homozygous state. Details ▾Hide ▴
Evidence considered
- Absent ATM kinase activity in homozygous patients (PMID:22213089)
- Absent ATM protein in homozygous patient (PMID:10873394)
Sources
BP2 No co-occurrence data in trans with a known pathogenic variant was available for scoring under the ATM VCEP PM3/BP2 table. Without such observations, BP2 points cannot be assigned. Details ▾Hide ▴
Still missing
- No trans co-occurrence data available
BP4 SpliceAI max delta score is 0.12, which is above the ATM VCEP BP4 splicing threshold of ≤0.1. REVEL score is not available as this is not a missense variant. Neither in-silico benign criterion threshold is met. Details ▾Hide ▴
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AATM VCEP PS1 applies to missense single-nucleotide substitutions (where splicing is ruled out for both alterations) or to splicing variants via the ATM PS1 splicing table. This variant is an in-frame deletion-insertion, not a missense SNV or a splicing variant. Details ▾Hide ▴
No further detail was recorded.
PS2 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
PM1 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM5 N/AATM VCEP PM5 applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_VS(RNA). This variant is an in-frame deletion-insertion without PTC and without significant splicing impact (SpliceAI max delta = 0.12). Details ▾Hide ▴
Evidence considered
- In-frame variant
- no PTC created
- SpliceAI max delta score = 0.12
- no significant splicing impact
Sources
PM6 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
PP4 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
PP5 VCEPNot included in ATM VCEP v1.5.0 criteria. Details ▾Hide ▴
No further detail was recorded.
BS2 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
BS4 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
BP1 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
BP3 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
BP5 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPMarked Not Applicable by ATM VCEP v1.5.0. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AATM VCEP BP7 is reserved for synonymous and deep intronic variants (further than +7 from donor or -21 from acceptor). This variant is an exonic in-frame deletion-insertion and does not qualify. Details ▾Hide ▴
No further detail was recorded.
PS5 N/ANot included in ATM VCEP v1.5.0 criteria. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.7875_7876delinsGC
- Protein (HGVS p.)
- NP_000042.3:p.(Asp2625_Ala2626delinsGluPro)
- GRCh38
- chr11:108332848 TG>GC
- GRCh37
- chr11:108203575 TG>GC
- ClinVar
- 3030
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ATM
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI max delta score for this variant is 0.12, below the ATM VCEP PP3 threshold of ≥0.2 for splicing variants. REVEL score is not available as this is not a missense variant. Neither in-silico criterion threshold is met. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.12 (<0.2 VCEP threshold)
- REVEL not available for in-frame indel
Sources
BP4 SpliceAI max delta score is 0.12, which is above the ATM VCEP BP4 splicing threshold of ≤0.1. REVEL score is not available as this is not a missense variant. Neither in-silico benign criterion threshold is met. Details ▾Hide ▴
BP7 N/AATM VCEP BP7 is reserved for synonymous and deep intronic variants (further than +7 from donor or -21 from acceptor). This variant is an exonic in-frame deletion-insertion and does not qualify. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).
8 paper records listed. 3 cited in the classification.
Cited in the classification
-
PMID 10873394 ↗Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity.Becker-Catania SG et al. · 2000 JunPatient AT152LA, homozygous for the 7875TG→GC mutation (encoding DA2625-2626EP), had no detectable ATM protein by Western blot analysis. This in-frame double substitution was among mutations associated with absent ATM protein, consistent with protein instability or degradation despite an intact reading frame.→ PS3 Names this variant
Source detail
patient AT152LA was homozygous for a 7875TG . GC mutation resulting in a change from aspartic acid-alanine to glutamic acid-proline at positions 2625 and 2626 (DA2625-2626EP)
Location Results, paragraph describing patients lacking ATM protein; Fig. 2
Context Western blot analysis of ATM protein in EBV-transformed lymphoblastoid cell lines; ATM detected with monoclonal antibody 3E8
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PMID 15054841 ↗Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations.Dörk T et al. · 2004 Apr 30A 60-year-old A-T patient was compound heterozygous for the double missense substitution 7875T>G/7876G>C (D2625E-A2626P) in exon 55 and a novel splice mutation (496+5G>A). Lymphoblastoid cells showed 10-20% residual ATM protein and markedly reduced radiation-induced ATM kinase activity towards p53 (approximately 2-fold increase vs >10-fold in controls), with poorly detectable nibrin phosphorylation.→ PS3 Names this variant
Source detail
the first is a double missense substitution, 7875T > G/7876G > C in exon 55, that gives rise to the amino acid changes D2625E and A2626P
Location Results, 'Mutation Analysis'; Abstract; Fig. 2
Context Western blot of ATM protein and phospho-p53(Ser-15) in EBV-transformed lymphoblastoid cells (AT15BER); radiation-induced phosphorylation measured 30 min after 6 Gy irradiation
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PMID 22213089 ↗Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.Verhagen MM et al. · 2012 MarThe c.7875_7876delTGinsGC (p.Asp2625_Ala2626delinsGluPro) variant was observed in 9 of 51 patients (13/95 alleles, from 7 families). Homozygous patients (14.I, 14.II, 15.I, 15.II) were classified as Group 2: ATM protein present but without detectable kinase activity toward downstream targets SMC1, KAP-1, and CREB. A compound heterozygous patient (patient 9) also showed absent kinase activity.→ PS3 Names this variant
Source detail
the c.7875_7876delTGinsGC mutation was observed in nine patients from seven families (13/95 alleles)
Location Results, Table 1; 'ATM mutations, ATM Protein Expression Levels, and ATM Kinase Activity'
Context Western blot analysis of ATM protein and kinase activity in lymphoblastoid cell lines; kinase activity assessed using phospho-specific antibodies against SMC1ser966, KAP-1ser824, Nbs1ser343, and CREBser121 after 5 Gy gamma irradiation
Other recorded publications
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PMID 10817650 ↗Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.Li A et al. · 2000Mutation screening study of A-T patients: PCR amplification and sequencing detected 77 mutations in 90 A-T chromosomes. NM_000051.4:c.7875_7876delinsGC was not identified in the available abstract.Does not name this variant
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PMID 10980530 ↗Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.Laake K et al. · 2000Among 37 unique ATM mutations identified in 41 Nordic A-T families, one double substitution in exon 55 (described as DA 2625-2627 EP) was observed. The amino acid changes introduce a proline residue predicted to cause a bend in the protein chain, in a region conserved between mouse and human, upstream of the kinase domain. This variant was found on 1 of 82 AT alleles.Names this variant
Quoted passage
one double substitution in exon 55, DA 2625-2627 EP, was seen upstream of the kinase domain of the ATM protein. These amino acids are in a stretch of 12 amino acids conserved between mouse and man. The amino acid changes lead to insertion of a proline residue, which introduces a bend in the protein chain.
Results, section 'The Spectrum of Mutations'; Table 3
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PMID 26635394 ↗RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins.Describes RBP-Var, a database of functional variants affecting RNA-binding protein interactions. Focuses on SNVs that alter RNA secondary structure. NM_000051.4:c.7875_7876delinsGC was not identified in this paper.Does not name this variant
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PMID 11104561 ↗Screening breast cancer patients for Norwegian ATM mutations.Laake K et al. · 2000Six Norwegian ATM founder mutations were screened in 483 breast cancer patients. The variant 7875-7876 TG/GC (this variant) was included in the mutation panel (Table 1) but was not detected among any of the 483 breast cancer patients. Only one carrier of any of the six mutations was found (the Norwegian founder mutation 3245-3247delATCinsTGAT).Names this variant
Quoted passage
7875-7876 TG/GC 55 Substitutions, DA2625-2627EP
Table 1; Results
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PMID 25037873 ↗Cognitive phenotype in ataxia-telangiectasia.Cognitive phenotype study of 22 A-T patients comparing early- and late-stage cerebellar disease. This paper examines neurocognitive features in A-T generally and does not report individual variant data. NM_000051.4:c.7875_7876delinsGC was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.120
Open source ↗
ClinVar
9 Pathogenic · 4 Likely pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/639508985
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3030/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108203575-TG-GC?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108332848-TG-GC?dataset…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-108332848-TG-GC
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.7875…
- OncoKB ↗www.oncokb.org/gene/ATM/D2625_A2626delinsEP
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.7875_7876delinsGC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (9 clinical laboratories) and as Likely pathogenic (4 clinical laboratories). (ClinVarID = 3030)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12).
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.