About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.5983G>T, p.(Glu1995Ter)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong
NM_000051.4:c.5983G>T is a nonsense variant (p.Glu1995Ter) in exon 40 of 63 of ATM, a gene where loss of function is a well-established disease mechanism for ataxia-telangiectasia. The premature termination codon lies well upstream of the final exon-exon junction and is predicted to trigger nonsense-mediated decay. The ATM VCEP v1.5 PVS1 decision tree was applied; the variant truncates the protein prior to the FAT domain (aa 2097–2488), PI3K domain (aa 2623–2974), and FATC domain (aa 3026–3055). The VCEP supplement (PMID:40580951, Table S1) classifies this variant as 'Non-functional' with a combined score of 0.960.
PM2Supporting
PM2 · supporting
NM_000051.4:c.5983G>T is absent from gnomAD v4.1 (0 alleles out of population database) and gnomAD v2.1. The allele frequency of 0.0% is well below the ATM VCEP v1.5 PM2_Supporting threshold of ≤0.001% in the gnomAD v4 dataset.
PM5Supporting
PM5 · supporting
NM_000051.4:c.5983G>T is a nonsense variant producing a premature termination codon at p.Glu1995Ter, which is upstream of p.Arg3047. Under ATM VCEP v1.5, PM5_Supporting applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PM5 supporting; maps to Pathogenic.
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.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53771051, n = 2 times).
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: 3 met · 4 not met · 4 not assessed · 18 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.5983G>T (p.Glu1995Ter) is a nonsense variant in exon 40 of 63 of ATM, a gene where loss of function is a well-established mechanism for autosomal recessive ataxia-telangiectasia. The premature termination codon lies well upstream of the final exon and is predicted to trigger nonsense-mediated decay, removing all critical C-terminal domains (FAT, PI3K, FATC). Under the ATM VCEP v1.5 PVS1 decision tree, this meets PVS1 at Very Strong strength.
The variant is absent from gnomAD v4.1 and v2.1 (0 alleles observed), meeting the ATM VCEP v1.5 PM2_Supporting threshold of allele frequency ≤0.001% in the gnomAD v4 dataset.
As a truncating variant with a premature termination codon at p.Glu1995, located upstream of p.Arg3047, PM5_Supporting applies per ATM VCEP v1.5 specifications.
No experimental functional data (PS3/BS3), case-control enrichment data (PS4), de novo observations (PS5), or co-segregation data (PP1) were identified for this specific variant in the reviewed literature. None of the three publications reviewed (PMID:27413114, PMID:30348496, PMID:30553448) mentioned NM_000051.4:c.5983G>T.
Applying the ATM VCEP v1.5 final classification rules (Richards et al. 2015 combination framework): PVS1 (Very Strong) plus two Supporting pathogenic criteria (PM2_Supporting, PM5_Supporting) satisfies Rule 4 (1 Pathogenic Very Strong + ≥2 Pathogenic Supporting), resulting in a final classification of Pathogenic.
No criteria match.
Met · 3
PVS1 Very strongNM_000051.4:c.5983G>T is a nonsense variant (p.Glu1995Ter) in exon 40 of 63 of ATM, a gene where loss of function is a well-established disease mechanism for ataxia-telangiectasia. The premature termination codon lies well upstream of the final exon-exon junction and is predicted to trigger nonsense-mediated decay. The ATM VCEP v1.5 PVS1 decision tree was applied; the variant truncates the protein prior to the FAT domain (aa 2097–2488), PI3K domain (aa 2623–2974), and FATC domain (aa 3026–3055). The VCEP supplement (PMID:40580951, Table S1) classifies this variant as 'Non-functional' with a combined score of 0.960. Details ▾Hide ▴
Evidence considered
- Nonsense variant at codon 1995 (E1995*) in exon 40 of 63 exons
- Predicted to trigger nonsense-mediated decay
- Truncation upstream of all critical C-terminal domains (FAT
- PI3K
- FATC)
- ATM VCEP v1.5 PVS1 decision tree applied
- VCEP Supplement Table S1 classifies as 'Non-functional'
Sources
vcep_atm_pvs1_1_5vcep_suppl_tables1_pmid_40580951pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_000051.4:c.5983G>T is absent from gnomAD v4.1 (0 alleles out of population database) and gnomAD v2.1. The allele frequency of 0.0% is well below the ATM VCEP v1.5 PM2_Supporting threshold of ≤0.001% in the gnomAD v4 dataset. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1 (AF = 0)
- Absent from gnomAD v2.1 (AF = 0)
- Frequency ≤0.001% per VCEP PM2_Supporting threshold
Sources
PM5 SupportingNM_000051.4:c.5983G>T is a nonsense variant producing a premature termination codon at p.Glu1995Ter, which is upstream of p.Arg3047. Under ATM VCEP v1.5, PM5_Supporting applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. Details ▾Hide ▴
Evidence considered
- Nonsense variant at p.Glu1995Ter
- upstream of the PM5 cutoff residue p.Arg3047
- ATM VCEP v1.5 PM5_Supporting rule for truncating variants upstream of p.Arg3047
Sources
Not met · 4 · evaluated, threshold not reached
PS4 No case-control study meeting ATM VCEP v1.5 PS4 criteria (p ≤ 0.05 AND odds ratio/hazard ratio/relative risk ≥2 OR lower 95% CI ≥1.5) was identified for this variant. The variant is present in ClinVar (Variation ID: 127398) with multiple clinical laboratories classifying it as Pathogenic for ataxia-telangiectasia, but ClinVar does not provide quantitative case enrichment data sufficient to satisfy PS4 under the VCEP framework. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 127398: classified as Pathogenic by multiple clinical labs
- No published case-control study with statistical enrichment data
Still missing
- No systematic case-control study with odds ratio or relative risk for this variant
- Exact case counts not available from ClinVar
Sources
PP1 No co-segregation data were identified for NM_000051.4:c.5983G>T in families with ataxia-telangiectasia. PP1 under ATM VCEP v1.5 requires segregation of the variant with disease in affected relatives (1 relative for Supporting, 2 for Moderate, ≥3 for Strong). None of the three reviewed publications contained pedigree or segregation data for this variant. Details ▾Hide ▴
Still missing
- No co-segregation data in families with ataxia-telangiectasia
- No pedigree studies involving this variant
Sources
274131143034849630553448
BA1 NM_000051.4:c.5983G>T is absent from gnomAD v4.1. The ATM VCEP v1.5 BA1 threshold requires a Grpmax Filtering AF >0.5% in the gnomAD v4 dataset. With an allele frequency of 0.0%, BA1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- Grpmax Filtering AF = 0%
- below the BA1 threshold of >0.5%
Sources
BS1 NM_000051.4:c.5983G>T is absent from gnomAD v4.1. The ATM VCEP v1.5 BS1 threshold requires a Grpmax Filtering AF >0.05% in the gnomAD v4 dataset. With an allele frequency of 0.0%, BS1 is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1
- Grpmax Filtering AF = 0%
- below the BS1 threshold of >0.05%
Sources
Not assessed · 4 · no assessment recorded
PS3 No experimental functional assay data were identified for NM_000051.4:c.5983G>T. The ATM VCEP Supplement Table S1 (PMID:40580951) lists this variant with a 'Non-functional' designation, but the evidence source is 'Computational prediction' (eDA), not experimental functional data. PS3 under ATM VCEP v1.5 requires experimental evidence of failure to rescue ATM-specific features (e.g., phosphorylation of ATM-specific targets) with or without radiosensitivity data. None of the three publications reviewed (PMID:27413114, PMID:30348496, PMID:30553448) mentioned this specific variant. Details ▾Hide ▴
Evidence considered
- VCEP Supplement Table S1 lists computational prediction only
- not experimental functional data
- No variant-specific functional evidence in reviewed literature
Still missing
- No experimental functional assay data for this specific variant in the literature
- No data on phosphorylation of ATM-specific targets or radiosensitivity rescue
Sources
274131143034849630553448
BS3 No experimental functional assay data demonstrating rescue of ATM function were identified for NM_000051.4:c.5983G>T. BS3 under ATM VCEP v1.5 requires experimental evidence that the variant rescues either an ATM-specific feature (e.g., phosphorylation of ATM-specific targets) with or without radiosensitivity. The VCEP Supplement Table S1 (PMID:40580951) is computational, not experimental. None of the three reviewed publications mentioned this specific variant. Details ▾Hide ▴
Evidence considered
- No experimental functional rescue data for this variant
- VCEP Supplement Table S1 provides computational predictions only
Still missing
- No experimental functional assay data demonstrating rescue of ATM function
- No variant-specific functional evidence in reviewed literature
Sources
274131143034849630553448
BP2 The ATM VCEP v1.5 BP2 point system requires observation of the variant in unaffected (non-A-T) individuals, scored by zygosity and phase relative to a pathogenic variant. No such data were identified for NM_000051.4:c.5983G>T in the reviewed literature or databases. Details ▾Hide ▴
Still missing
- No proband-level data for this variant in unaffected individuals
- No observations in trans or homozygous state in non-A-T individuals
Sources
274131143034849630553448
PS5 No de novo occurrence data were identified for NM_000051.4:c.5983G>T. PS5 requires confirmation that the variant occurred de novo with both parental samples confirmed to be negative. None of the three reviewed publications addressed de novo occurrence of this variant. Details ▾Hide ▴
Still missing
- No de novo occurrence data identified in the literature or databases
Sources
274131143034849630553448
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 per ATM VCEP v1.5 applies only to missense changes (requiring splice exclusion for both alterations) or splicing variants (using the ATM PS1 Splicing table). This variant is a nonsense change and neither the missense nor splicing comparator framework applies. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rule restricted to missense and splicing variants
Sources
vcep_atm_ps1_1_5
PS2 VCEPPS2 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
PM1 VCEPPM1 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
PM3 N/APM3 was excluded from this assessment per adjudication instructions. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 per ATM VCEP v1.5 is restricted to stop-loss variants. This variant is a stop-gain (nonsense), not a stop-loss. Details ▾Hide ▴
No further detail was recorded.
PM6 VCEPPM6 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
PP2 VCEPPP2 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
PP3 N/APP3 per ATM VCEP v1.5 applies to missense variants with REVEL >0.7333 or splicing variants with SpliceAI ≥0.2. This variant is a nonsense change; REVEL score is not available and SpliceAI max delta is 0.00. Neither the missense nor splicing PP3 criteria apply to a nonsense variant. Details ▾Hide ▴
Evidence considered
- Variant is nonsense
- not missense or splicing
- SpliceAI max delta = 0.00 (no predicted splice impact)
- REVEL score not available for nonsense variant
Sources
PP4 VCEPPP4 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
BS2 VCEPBS2 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
BS4 VCEPBS4 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
BP3 VCEPBP3 is not applicable per ATM VCEP v1.5 specifications (in-frame deletions/insertions in non-repeat regions). Details ▾Hide ▴
No further detail was recorded.
BP4 N/ABP4 per ATM VCEP v1.5 is defined for missense variants (REVEL ≤0.249) and splicing variants (SpliceAI ≤0.1). This variant is a nonsense change with a definitive impact on the protein product via premature termination; the SpliceAI score of 0.00 is irrelevant to the variant's primary mechanism, and applying BP4 for absent splicing impact would be inappropriate when PVS1 already addresses the null variant effect. Details ▾Hide ▴
Evidence considered
- Variant is nonsense
- not missense or splicing
- SpliceAI max delta = 0.00
- PVS1 addresses the null effect
Sources
BP5 VCEPBP5 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
BP6 VCEPBP6 is not applicable per ATM VCEP v1.5 specifications. Details ▾Hide ▴
BP7 N/ABP7 per ATM VCEP v1.5 applies to synonymous and deep intronic variants (further than +7 at donor sites and further than -21 at acceptor sites). This variant is a nonsense change and does not meet the BP7 criteria. Details ▾Hide ▴
Evidence considered
- Variant is nonsense
- BP7 is restricted to synonymous and deep intronic variants per VCEP
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.5983G>T
- Protein (HGVS p.)
- NP_000042.3:p.(Glu1995Ter)
- GRCh38
- chr11:108312475 G>T
- GRCh37
- chr11:108183202 G>T
- COSMIC
- COSV53771051
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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.635
How the predictions were used
PP3 N/APP3 per ATM VCEP v1.5 applies to missense variants with REVEL >0.7333 or splicing variants with SpliceAI ≥0.2. This variant is a nonsense change; REVEL score is not available and SpliceAI max delta is 0.00. Neither the missense nor splicing PP3 criteria apply to a nonsense variant. Details ▾Hide ▴
Evidence considered
- Variant is nonsense
- not missense or splicing
- SpliceAI max delta = 0.00 (no predicted splice impact)
- REVEL score not available for nonsense variant
Sources
BP4 N/ABP4 per ATM VCEP v1.5 is defined for missense variants (REVEL ≤0.249) and splicing variants (SpliceAI ≤0.1). This variant is a nonsense change with a definitive impact on the protein product via premature termination; the SpliceAI score of 0.00 is irrelevant to the variant's primary mechanism, and applying BP4 for absent splicing impact would be inappropriate when PVS1 already addresses the null variant effect. Details ▾Hide ▴
Evidence considered
- Variant is nonsense
- not missense or splicing
- SpliceAI max delta = 0.00
- PVS1 addresses the null effect
Sources
BP7 N/ABP7 per ATM VCEP v1.5 applies to synonymous and deep intronic variants (further than +7 at donor sites and further than -21 at acceptor sites). This variant is a nonsense change and does not meet the BP7 criteria. Details ▾Hide ▴
Evidence considered
- Variant is nonsense
- BP7 is restricted to synonymous and deep intronic variants per VCEP
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.634849.
3 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 27413114 ↗ATM Mutations in Cancer: Therapeutic Implications.No paper-specific finding is recorded.
-
PMID 30348496 ↗Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.No paper-specific finding is recorded.
-
PMID 30553448 ↗Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.No paper-specific finding is recorded.
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 0.000
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_000051.4%3Ac.5983G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108183202-G-T?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108312475-G-T?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.5983…
- OncoKB ↗www.oncokb.org/gene/ATM/E1995*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122742821
- 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.
ClinVar
This variant is present in ClinVar (Variation ID: 4077029); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.634849.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53771051, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.