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ATMc.9041_9042delLikely pathogenic
Print report
Variant interpretation report

ATM c.9041_9042del, p.(Gln3014ArgfsTer48)

NM_000051.4:c.9041_9042del NP_000042.3:p.(Gln3014ArgfsTer48) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

No gene-level summary was recorded for this case.

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
PVS1Very strong
PVS1 · very strong

This frameshift deletion (c.9041_9042del) introduces a premature termination codon at p.Gln3014ArgfsTer48 in exon 63 of ATM. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay (PTC is not in the last exon and is >55 nt upstream of the final exon-exon junction). The truncation occurs upstream of the p.Arg3047 critical C-terminal threshold defined by the ATM VCEP v1.5.0 PVS1 decision tree, supporting PVS1 at Very Strong strength.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v4.1 (allele count 0). Per ATM VCEP v1.5.0, a frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. The variant is also absent from gnomAD v2.1 and gnomAD-Canada.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (1 Pathogenic.Very Strong + 1 Pathogenic.Supporting) with applied criteria: PVS1 very strong, PM2 supporting; maps to Likely Pathogenic.

02The sources

Evidence at a glance

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

No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

No listed criterion applied
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
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 3 not met · 5 not assessed · 18 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at Very Strong strength: NM_000051.4:c.9041_9042del is a frameshift deletion resulting in a premature termination codon (p.Gln3014ArgfsTer48) upstream of the p.Arg3047 threshold in a gene where loss of function is an established disease mechanism. The PTC is NMD-competent per the ClinGen SVI PVS1 framework and the ATM VCEP PVS1 decision tree.

PM2 is met at Supporting strength: this variant is absent from gnomAD v4.1 (allele count 0), meeting the ATM VCEP threshold of ≤0.001% allele frequency in gnomAD v4.

No benign or conflicting evidence was identified: BA1 and BS1 are not met (variant absent from gnomAD); PS3/BS3 functional evidence was sought but no variant-specific functional data were found in the reviewed literature or VCEP reference tables.

Under the ATM VCEP v1.5.0 final combination rules, Rule 19 is triggered: 1 Very Strong pathogenic criterion (PVS1) + 1 Supporting pathogenic criterion (PM2_Supporting) yields a classification of Likely Pathogenic.

Met · 2

PVS1 Very strongThis frameshift deletion (c.9041_9042del) introduces a premature termination codon at p.Gln3014ArgfsTer48 in exon 63 of ATM. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay (PTC is not in the last exon and is >55 nt upstream of the final exon-exon junction). The truncation occurs upstream of the p.Arg3047 critical C-terminal threshold defined by the ATM VCEP v1.5.0 PVS1 decision tree, supporting PVS1 at Very Strong strength. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion creating premature termination codon at position 3061
  • ATM loss-of-function is established disease mechanism for Ataxia-Telangiectasia and hereditary breast/ovarian/pancreatic cancer
  • PTC is NMD-competent per ClinGen SVI PVS1 framework (not in terminal exon
  • not within 55 nt of last exon-exon junction)
  • Truncation occurs at codon 3014
  • upstream of the p.Arg3047 threshold defined by ATM VCEP PVS1 decision tree
Sources
cspec ↗pvs1_generic_framework ↗vcep_atm_pvs1_1_5
PM2 SupportingThis variant is absent from gnomAD v4.1 (allele count 0). Per ATM VCEP v1.5.0, a frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. The variant is also absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (0 alleles
  • 0 homozygotes)
  • Absent from gnomAD v2.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v4 ↗gnomad_v2 ↗cspec ↗

Not met · 3 · evaluated, threshold not reached

PM5 The ATM VCEP PM5 rule states: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.' The premature termination codon created by this variant is at position 3061 (p.Gln3014ArgfsTer48), which is downstream of the p.Arg3047 threshold. Per strict reading of the VCEP rule, the PTC position rather than the variant start position determines eligibility; therefore PM5 does not apply. Details ▾Hide ▴
Evidence considered
  • Frameshift starts at codon 3014 but PTC occurs at codon 3061
  • Position 3061 is downstream of p.Arg3047 (position 3047)
Still missing
  • VCEP curators may wish to review whether the variant position (3014 < 3047) rather than PTC position was intended for PM5 applicability
Sources
cspec ↗
BA1 Per ATM VCEP v1.5.0, BA1 requires Grpmax Filtering AF >0.5% in gnomAD v4. The variant is absent from gnomAD v4.1 (allele count 0), which is far below the BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (AF = 0)
Sources
gnomad_v4 ↗cspec ↗
BS1 Per ATM VCEP v1.5.0, BS1 requires Grpmax Filtering AF >0.05% in gnomAD v4. The variant is absent from gnomAD v4.1 (allele count 0), which is far below the BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (AF = 0)
Sources
gnomad_v4 ↗cspec ↗

Not assessed · 5 · no assessment recorded

PS3 No variant-specific functional evidence was identified for NM_000051.4:c.9041_9042del. Three PMIDs (27413114, 30348496, 30553448) were reviewed in full text; all discuss ATM function at the gene level but none studies this specific variant. ATM VCEP functional assay reference tables (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) list approved PS3/BS3 assay frameworks but do not include data for this variant. Suppl_TableS1 (PMID:40580951) contains only SNV functional scores and does not include this deletion. Details ▾Hide ▴
Evidence considered
  • Three ATM functional studies reviewed
  • none contained variant-specific evidence
Still missing
  • No variant-specific functional assay data (kinase activity
  • radiosensitivity) available
  • Functional studies of this exact variant would be needed to apply PS3
Sources
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951274131143034849630553448
PS4 No case-control studies or systematic case observation data were identified for this specific variant. An exploratory literature search found no curated case counts comparing prevalence in affected individuals versus controls. The variant is absent from gnomAD, which is consistent with rarity but does not independently satisfy PS4 without case data. Details ▾Hide ▴
Still missing
  • No case-control studies with p-value
  • odds ratio
  • or relative risk data per ATM VCEP PS4 rule
  • No cohort studies reporting observation counts of this variant in affected individuals
PP1 No cosegregation data were identified for this variant. Per ATM VCEP, PP1 for the recessive A-T condition requires segregation in affected relatives (1/2/3+ affected relatives for Supporting/Moderate/Strong). No family studies reporting this variant were found. Details ▾Hide ▴
Still missing
  • No family segregation studies available for this variant
Sources
cspec ↗
BS3 No variant-specific functional evidence demonstrating rescue of ATM function was identified. Three PMIDs (27413114, 30348496, 30553448) were reviewed in full text; all discuss ATM generally but none studies this specific variant. Per ATM VCEP, BS3 requires evidence that the variant rescues ATM-specific features and/or radiosensitivity. No such data are available for this variant. Details ▾Hide ▴
Evidence considered
  • Three ATM functional studies reviewed
  • none contained variant-specific evidence
Still missing
  • No functional rescue data for this specific variant
Sources
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1274131143034849630553448
BP2 No data were identified regarding observation of this variant in cis or trans with other pathogenic ATM variants. BP2 requires points from the ATM PM3/BP2 table based on observations in unaffected individuals. No such observations are available for this variant. Details ▾Hide ▴
Still missing
  • No data on co-occurrence in cis/trans with other ATM pathogenic variants in unaffected individuals
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/AATM VCEP PS1 rules apply only to missense or splicing variants at the same nucleotide/residue. This variant is a frameshift deletion. Details ▾Hide ▴
Sources
vcep_atm_ps1_1_5
PS2 VCEPPS2 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
PM1 VCEPPM1 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
PM4 N/APer ATM VCEP v1.5.0, PM4 is restricted to stop-loss variants. This variant is a frameshift deletion, not a stop-loss variant. Details ▾Hide ▴
Sources
cspec ↗
PM6 VCEPPM6 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPPP2 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
PP3 N/APer ATM VCEP v1.5.0, PP3 applies to missense variants (REVEL >0.7333) or splicing variants (SpliceAI ≥0.2). This is a frameshift deletion; REVEL and BayesDel scores are not applicable, and SpliceAI returned no delta scores for this variant. In silico prediction tools are not designed to assess the functional impact of frameshift variants. Details ▾Hide ▴
Sources
cspec ↗spliceai ↗
PP4 VCEPPP4 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPPP5 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
BS2 VCEPBS2 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
BS4 VCEPBS4 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPBP1 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPBP3 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
BP4 N/APer ATM VCEP v1.5.0, BP4 applies to missense variants (REVEL ≤0.249) or splicing variants (SpliceAI ≤0.1). This is a frameshift deletion; in silico missense and splicing predictors are not applicable to this variant class. Details ▾Hide ▴
Sources
cspec ↗
BP5 VCEPBP5 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
BP6 VCEPBP6 is explicitly marked Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/APer ATM VCEP v1.5.0, BP7 applies to synonymous and deep intronic variants. This is a frameshift deletion. Details ▾Hide ▴
Sources
cspec ↗
PS5 N/AThe ATM VCEP does not define PS5 criteria. The supporting counterpart (PP5) is explicitly marked Not Applicable by the VCEP, consistent with the framework's approach of not assigning weight to ClinVar classifications without accessible primary evidence. Details ▾Hide ▴
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.9041_9042del
Protein (HGVS p.)
NP_000042.3:p.(Gln3014ArgfsTer48)
GRCh38
chr11:108365377 CAA>C
GRCh37
chr11:108236104 CAA>C

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 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.

Open the gnomAD-Canada detail page →

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APer ATM VCEP v1.5.0, PP3 applies to missense variants (REVEL >0.7333) or splicing variants (SpliceAI ≥0.2). This is a frameshift deletion; REVEL and BayesDel scores are not applicable, and SpliceAI returned no delta scores for this variant. In silico prediction tools are not designed to assess the functional impact of frameshift variants. Details ▾Hide ▴
Sources
cspec ↗spliceai ↗
BP4 N/APer ATM VCEP v1.5.0, BP4 applies to missense variants (REVEL ≤0.249) or splicing variants (SpliceAI ≤0.1). This is a frameshift deletion; in silico missense and splicing predictors are not applicable to this variant class. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/APer ATM VCEP v1.5.0, BP7 applies to synonymous and deep intronic variants. This is a frameshift deletion. Details ▾Hide ▴
Sources
cspec ↗

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

  • ATM Mutations in Cancer: Therapeutic Implications.
    No paper-specific finding is recorded.
    PMID 27413114 ↗
  • 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 30348496 ↗
  • Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
    No paper-specific finding is recorded.
    PMID 30553448 ↗

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 Captured SpliceAI source record 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

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 absent from ClinVar.

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.