About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.7875T>G, p.(Asp2625Glu)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000051.4:c.7875T>G is present in gnomAD v4.1 at an allele frequency of 6.82 × 10⁻⁶ (0.00068%; 11/1,613,262 alleles), which is below the ATM VCEP PM2_Supporting threshold of ≤0.001%. The variant is absent from gnomAD-Canada and observed at 3.99 × 10⁻⁶ in gnomAD v2.1 (1/250,866 alleles).
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: 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
11 / 1,613,262 alleles
gnomAD v4.1: 11 / 1,613,262 alleles. Recorded AF 6.81848e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98619e-06; MAF= 0.00040%, 1/250866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81663e-06; MAF= 0.00088%, 1/113422 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Pathogenic. ClinVar API review status: criteria provided, single submitter.
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.
No listed criterion applied
OncoKB ↗
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.
26 criteria with recorded statuses: 1 met · 10 not met · 0 not assessed · 15 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.7875T>G (p.Asp2625Glu) is a missense variant in exon 53 of ATM, observed at extremely low frequency in gnomAD v4.1 (AF = 6.82 × 10⁻⁶, 11/1,613,262 alleles), meeting PM2_Supporting.
In silico predictions are inconclusive: REVEL score (0.373) falls between the VCEP PP3 threshold (>0.7333) and BP4 threshold (≤0.249), and SpliceAI predicts no splicing impact (max delta = 0.07).
The variant is classified as 'Functional' (High confidence) in the ATM SNV combined-score table (PMID 40580951), reflecting in silico composite prediction rather than experimental functional data; no variant-specific functional assays are available.
ClinVar reports this variant as Pathogenic (1 submitter, criteria provided, single submitter); however, the VCEP does not use PP5/BP6, and no independent case-level or functional evidence corroborates this classification.
With only PM2_Supporting met and no other criteria satisfied, this variant does not reach a Likely Pathogenic or Likely Benign classification under the ACMG/AMP combination rules and is classified as a Variant of Uncertain Significance.
No criteria match.
Met · 1
PM2 SupportingNM_000051.4:c.7875T>G is present in gnomAD v4.1 at an allele frequency of 6.82 × 10⁻⁶ (0.00068%; 11/1,613,262 alleles), which is below the ATM VCEP PM2_Supporting threshold of ≤0.001%. The variant is absent from gnomAD-Canada and observed at 3.99 × 10⁻⁶ in gnomAD v2.1 (1/250,866 alleles). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 6.82e-06 (≤0.001% threshold met)
- grpmax FAF = 5e-06. Absent from gnomAD-Canada.
Sources
Not met · 10 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change resulting in the same amino acid substitution (p.Asp2625Glu) with a prior pathogenic or likely pathogenic classification. While c.7875T>A also encodes p.Asp2625Glu, it lacks a ClinVar classification and is not established as pathogenic or likely pathogenic. No qualifying comparator variant exists. Details ▾Hide ▴
Evidence considered
- c.7875T>A (same amino acid change D2625E) has no ClinVar classification
- no P/LP comparator available.
Still missing
- No alternate nucleotide variant at codon 2625 encoding p.Asp2625Glu with a P/LP classification.
Sources
vcep_atm_ps1_1_5vcep_suppl_tables1_pmid_40580951
PS3 No variant-specific experimental functional assay data are available. ATM VCEP PS3 requires rescue assay evidence (failure to rescue ATM-specific phosphorylation targets and/or radiosensitivity). The Suppl_TableS1 classification of 'Functional' reflects in silico composite prediction, not experimental functional data. No publications with variant-specific functional assays were identified. Details ▾Hide ▴
Evidence considered
- Suppl_TableS1 'Functional' classification is computational prediction
- not experimental functional evidence. The ATM kinase activity and radiosensitivity reference tables do not list this variant.
Still missing
- No variant-specific functional assay addressing ATM phosphorylation targets or radiosensitivity rescue.
Sources
PS4 No case-control studies demonstrating significantly increased prevalence of NM_000051.4:c.7875T>G in affected individuals compared to controls are available. The ClinVar submission is from a single clinical laboratory without published case-level data. Details ▾Hide ▴
PP1 No co-segregation data are available for NM_000051.4:c.7875T>G. ATM VCEP PP1 applies only to autosomal recessive (A-T) conditions and requires affected relatives to carry both variants identified in the proband. No segregation studies have been published for this variant. Details ▾Hide ▴
Evidence considered
- No segregation data available in the literature.
Still missing
- No family studies or co-segregation data for this variant.
Sources
PP3 REVEL score is 0.373, below the ATM VCEP PP3 threshold of >0.7333. SpliceAI max delta is 0.07, below the splicing threshold of ≥0.2. Multiple computational predictors (REVEL, BayesDel −0.137, AlphaMissense 0.164, EVE 0.312) do not reach the consensus threshold for a deleterious prediction under the VCEP rules. Details ▾Hide ▴
Evidence considered
- REVEL = 0.373 (<0.7333 threshold)
- BayesDel = −0.137
- SpliceAI max delta = 0.07
- AlphaMissense = 0.164
- EVE = 0.312.
Sources
BA1 gnomAD v4.1 grpmax filtering AF is 5 × 10⁻⁶ (0.0005%), well below the ATM VCEP BA1 threshold of >0.5%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 5e-06 (threshold >0.5% not met).
Sources
BS1 gnomAD v4.1 grpmax filtering AF is 5 × 10⁻⁶ (0.0005%), well below the ATM VCEP BS1 threshold of >0.05%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF = 5e-06 (threshold >0.05% not met).
Sources
BS3 No variant-specific experimental functional studies demonstrating normal protein function or rescue of ATM-specific features are available. The ATM kinase activity and radiosensitivity reference tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) do not include this variant. Details ▾Hide ▴
Evidence considered
- No experimental functional data demonstrating benign effect. Variant not listed in VCEP kinase activity or radiosensitivity reference tables.
Still missing
- No experimental functional studies addressing rescue of ATM-specific features or radiosensitivity.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP2 No evidence of NM_000051.4:c.7875T>G occurring in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual aged ≥18 years. No points can be assigned under the ATM PM3/BP2 table. Details ▾Hide ▴
Evidence considered
- No co-occurrence data in unaffected individuals available.
Still missing
- No phase-known co-occurrence data in unaffected individuals.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
BP4 REVEL score is 0.373, above the ATM VCEP BP4 threshold of ≤0.249 for missense variants. Although SpliceAI predicts no splicing impact (max delta 0.07 ≤ 0.1), the REVEL score does not support a benign computational prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.373 (>0.249 threshold for BP4). SpliceAI = 0.07 (≤0.1
- no splice impact). BayesDel = −0.137.
Sources
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is applicable only to null variants (nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, exon deletion). NM_000051.4:c.7875T>G is a missense variant (p.Asp2625Glu) and does not fall within the ATM PVS1 decision tree. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant type eligible for PVS1 under the ATM VCEP decision tree.
Sources
pvs1_gene_contextpvs1_variant_assessmentvcep_atm_pvs1_1_5
PS2 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use for AD or AR disease — informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase. Details ▾Hide ▴
PM1 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use — benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time. Details ▾Hide ▴
PM5 N/AATM VCEP PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants meeting specific criteria. The VCEP explicitly states: 'Do not use for missense changes.' NM_000051.4:c.7875T>G is a missense variant (p.Asp2625Glu). Details ▾Hide ▴
Evidence considered
- Missense variant
- VCEP PM5 rules exclude missense changes.
Sources
cspec ↗pm5_candidates
PM6 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use for AD or AR disease — informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase. Details ▾Hide ▴
PP2 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use — ATM does not have a defined low rate of missense benign variation. Details ▾Hide ▴
PP4 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use — breast cancer has multiple genetic etiologies, and for A-T, phenotype evidence is built into the PM3/BP2 table. Details ▾Hide ▴
PP5 VCEPCSPEC HBOP ATM VCEP v1.5.0: Not Applicable for this VCEP — this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS2 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use — ATM has incomplete penetrance. Details ▾Hide ▴
BS4 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use — co-segregation analysis in low-penetrance genes can lead to false positives; informative instances of lack of co-segregation in A-T families are too rare. Details ▾Hide ▴
BP1 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use — missense pathogenic variants are known for ATM. Details ▾Hide ▴
BP5 VCEPCSPEC HBOP ATM VCEP v1.5.0: Do not use — cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype; ATM has low penetrance. Details ▾Hide ▴
BP6 VCEPCSPEC HBOP ATM VCEP v1.5.0: Not Applicable for this VCEP — this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP7 N/ABP7 is applicable only to synonymous and deep intronic variants (intronic variants beyond +7 at donor and −21 at acceptor). NM_000051.4:c.7875T>G is a missense variant (p.Asp2625Glu) and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and deep intronic variants.
Sources
PS5 N/APS5 is not included in the ClinGen HBOP ATM VCEP v1.5.0 criteria set. The VCEP review committee recommends against using PP5/BP6, and PS5 falls into the same category of relying on unverified external classifications. Details ▾Hide ▴
Evidence considered
- Not a VCEP-adopted criterion
- equivalent logic to PP5 which is explicitly not for use.
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.7875T>G
- Protein (HGVS p.)
- NP_000042.3:p.(Asp2625Glu)
- GRCh38
- chr11:108332848 T>G
- GRCh37
- chr11:108203575 T>G
- ClinVar
- 802788
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
11 / 1,613,262 alleles
AF 6.82e-06 · 0 homozygotes · FAF 5e-06
gnomAD v2.1
1 / 250,866 alleles
AF 3.99e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.8e-06 · 11 / 1,613,262 alleles · 0 hom · FAF 5e-06
| European (non-Finnish)11 / 1,179,706 | 9.3e-06 |
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 4e-06 · 1 / 250,866 alleles · 0 hom
| European (non-Finnish)1 / 113,422 | 8.8e-06 |
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= 6.81848e-06; MAF= 0.00068%, 11/1613262 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.32436e-06; MAF= 0.00093%, 11/1179706 alleles, homozygotes = 0); grpmax FAF= 5e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98619e-06; MAF= 0.00040%, 1/250866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81663e-06; MAF= 0.00088%, 1/113422 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.373
- BayesDel
- -0.137
How the predictions were used
PP3 REVEL score is 0.373, below the ATM VCEP PP3 threshold of >0.7333. SpliceAI max delta is 0.07, below the splicing threshold of ≥0.2. Multiple computational predictors (REVEL, BayesDel −0.137, AlphaMissense 0.164, EVE 0.312) do not reach the consensus threshold for a deleterious prediction under the VCEP rules. Details ▾Hide ▴
Evidence considered
- REVEL = 0.373 (<0.7333 threshold)
- BayesDel = −0.137
- SpliceAI max delta = 0.07
- AlphaMissense = 0.164
- EVE = 0.312.
Sources
BP4 REVEL score is 0.373, above the ATM VCEP BP4 threshold of ≤0.249 for missense variants. Although SpliceAI predicts no splicing impact (max delta 0.07 ≤ 0.1), the REVEL score does not support a benign computational prediction. Details ▾Hide ▴
Evidence considered
- REVEL = 0.373 (>0.249 threshold for BP4). SpliceAI = 0.07 (≤0.1
- no splice impact). BayesDel = −0.137.
Sources
BP7 N/ABP7 is applicable only to synonymous and deep intronic variants (intronic variants beyond +7 at donor and −21 at acceptor). NM_000051.4:c.7875T>G is a missense variant (p.Asp2625Glu) and does not qualify. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and deep intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.373. BayesDel score = -0.137386.
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 20301317 ↗Hereditary Ataxia Overview.Adam MP et al. · 1993GeneReviews entry on Hereditary Ataxia Overview. Broad review of hereditary ataxia disorders including ataxia telangiectasia. No variant-specific discussion of NM_000051.4:c.7875T>G.Does not name this variant
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PMID 20301790 ↗Ataxia-Telangiectasia.Adam MP et al. · 1993GeneReviews entry on Ataxia-Telangiectasia. Provides gene-level overview of ATM-associated disease, clinical features, and management. Gene-level resource; specific ATM variant NM_000051.4:c.7875T>G was not identified in the available metadata.Does not name this variant
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PMID 24418350 ↗EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.van de Warrenburg BP et al. · 2014EFNS/ENS consensus guideline on the diagnosis and management of chronic ataxias in adulthood. Mentions ataxia telangiectasia as a recessive ataxia disorder and provides general diagnostic recommendations, but does not discuss specific ATM variants.Does not name this variant
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PMID 20050888 ↗EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.Gasser T et al. · 2010EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. Provides testing recommendations for hereditary ataxias including ATM-related disorders at the gene level. Does not discuss specific ATM missense variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
11 / 1,613,262 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.070
Open source ↗
ClinVar
1 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/802788/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108203575-T-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108332848-T-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-108332848-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.7875…
- OncoKB ↗www.oncokb.org/gene/ATM/D2625E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.7875T%3EG
- 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
This variant is present in gnomAD v4.1 (AF= 6.81848e-06; MAF= 0.00068%, 11/1613262 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.32436e-06; MAF= 0.00093%, 11/1179706 alleles, homozygotes = 0); grpmax FAF= 5e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98619e-06; MAF= 0.00040%, 1/250866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.81663e-06; MAF= 0.00088%, 1/113422 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 802788)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.373. BayesDel score = -0.137386.
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.