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).1 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%).2 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.3 No benign criteria were met. The available evidence yields PS3_Supporting and PM2_Supporting, totaling two pathogenic supporting criteria.
ATM
Final classification
VUS
ATM c.7875_7876delinsGC · p.Asp2625_Ala2626delinsGluPro
ATM
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.
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.
Classification rationale
PS3PM2
VUS
ATM c.7875_7876delinsGC
PS3 + PM2
→
VUS
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
supporting
Pathogenic
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.
Loss of ATM kinase activity in homozygous state (PMID:22213089Group 2 patients)Absence of detectable ATM protein in homozygous patient AT152LA (PMID:10873394)
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v4.1 (grpmax FAF = null)Absent from gnomAD v2.1Absent from gnomAD-Canada v1.0
Assessed · not applied
Pathogenic
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).
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.
PM4
ATM VCEP PM4 is reserved for stop-loss variants.
PP1
No segregation data available.
PP3
SpliceAI max delta score for this variant is 0.12, below the ATM VCEP PP3 threshold of ≥0.2 for splicing variants.
Benign
BA1
Variant is absent from gnomAD v4.1.
BS1
Variant is absent from gnomAD v4.1.
BS3
Functional evidence demonstrates loss of ATM function (absent kinase activity, absent protein), not rescue.
BP2
No co-occurrence data in trans with a known pathogenic variant was available for scoring under the ATM VCEP PM3/BP2 table.
BP4
SpliceAI max delta score is 0.12, which is above the ATM VCEP BP4 splicing threshold of ≤0.1.
N/A · 16
PS1 · PS2 · PM1 · PM3 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
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.
Ataxia-telangiectasia: phenotype/genotype studies of ATM protein expression, mutations, and radiosensitivity.
Searched
7875TG7875TG.GCDA2625DA2625-2626EPAT152LA
Found
Patient 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.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific protein expression data confirmed; absence of ATM protein supports PS3_Supporting assessment.
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 · full text
Slow progression of ataxia-telangiectasia with double missense and in frame splice mutations.
Searched
7875T>G7876G>CD2625EA2626Pdouble missense
Found
A 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.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific functional data confirmed in compound heterozygous context; reduced kinase activity consistent with loss of ATM function, supporting PS3 assessment.
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 · full text
Presence of ATM protein and residual kinase activity correlates with the phenotype in ataxia-telangiectasia: a genotype-phenotype study.
Searched
c.7875_7876delTGinsGCc.7875_7876delTGinsGCAsp2625_Ala2626delinsGluPro7875
Found
The 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.
Variant
✓ Names this variant — characterised directly
Applied to
→PS3 supports · met
Why
Variant-specific functional data demonstrating loss of ATM kinase activity in homozygous state; directly supports PS3_Supporting assessment.
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 · full text
Sources & reference links
9Sources
Triaged references · 5 PMIDs not cited in assessment
10817650 ↗
Mutations at the ataxia-telangiectasia locus and clinical phenotypes of A-T patients.
CLINVAR
10980530 ↗
Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.
CLINVAR
26635394 ↗
RBP-Var: a database of functional variants involved in regulation mediated by RNA-binding proteins.
CLINVAR