ATMc.5164delPathogenic

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Variant interpretation report

ATM c.5164del, p.(Leu1722TrpfsTer2)

NM_000051.4:c.5164del NP_000042.3:p.(Leu1722TrpfsTer2) View identifiers

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.

About ATM

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen ATM VCEP v1.5.0
Pipeline record: 8 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000051.4:c.5164del is a frameshift deletion resulting in a premature termination codon at p.(Leu1722TrpfsTer2), well upstream of the most C-terminal pathogenic residue p.Arg3047. Under the ATM HBOP VCEP v1.5.0 PVS1 decision tree (adapted from PMID:30192042), this null variant in exon 34 of 63 is predicted to undergo nonsense-mediated decay and meets criteria for PVS1 at Very_Strong strength. Loss of function is an established disease mechanism for ATM in both autosomal recessive ataxia-telangiectasia and autosomal dominant cancer predisposition.
PM2 (supporting): This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), satisfying the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting. Absence from large population databases supports pathogenicity.
PM5 (supporting): Under the ATM VCEP v1.5.0, PM5_Supporting is applied to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant creates a PTC at codon 1723, which is well upstream of p.Arg3047 (the most C-terminal pathogenic residue per the VCEP).

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.5164del is a frameshift deletion resulting in a premature termination codon at p.(Leu1722TrpfsTer2), well upstream of the most C-terminal pathogenic residue p.Arg3047. Under the ATM HBOP VCEP v1.5.0 PVS1 decision tree (adapted from PMID:30192042), this null variant in exon 34 of 63 is predicted to undergo nonsense-mediated decay and meets criteria for PVS1 at Very_Strong strength. Loss of function is an established disease mechanism for ATM in both autosomal recessive ataxia-telangiectasia and autosomal dominant cancer predisposition.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), satisfying the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting. Absence from large population databases supports pathogenicity.

PM5Supporting

PM5 · supporting

Under the ATM VCEP v1.5.0, PM5_Supporting is applied to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant creates a PTC at codon 1723, which is well upstream of p.Arg3047 (the most C-terminal pathogenic residue per the VCEP).

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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. 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

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

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000051.4:c.5164del (p.Leu1722TrpfsTer2) is a frameshift deletion in ATM creating a premature termination codon at amino acid 1723, well upstream of the most C-terminal pathogenic residue p.Arg3047. Loss of function is an established disease mechanism for ATM, and this null variant is predicted to undergo nonsense-mediated decay, satisfying PVS1 at Very_Strong strength per the ClinGen HBOP VCEP v1.5.0 ATM PVS1 decision tree.

This variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles observed), meeting the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting.

The variant creates a premature termination codon at codon 1723, upstream of p.Arg3047, satisfying the ATM VCEP v1.5.0 criterion for PM5_Supporting, which applies to frameshifting or truncating variants with PTCs upstream of this boundary.

Applying the ClinGen HBOP VCEP v1.5.0 ACMG/AMP combination rules: 1 Very_Strong (PVS1) + 2 Supporting (PM2, PM5) satisfies Rule 4, resulting in a classification of Pathogenic.

Met · 3

PVS1 Very strongNM_000051.4:c.5164del is a frameshift deletion resulting in a premature termination codon at p.(Leu1722TrpfsTer2), well upstream of the most C-terminal pathogenic residue p.Arg3047. Under the ATM HBOP VCEP v1.5.0 PVS1 decision tree (adapted from PMID:30192042), this null variant in exon 34 of 63 is predicted to undergo nonsense-mediated decay and meets criteria for PVS1 at Very_Strong strength. Loss of function is an established disease mechanism for ATM in both autosomal recessive ataxia-telangiectasia and autosomal dominant cancer predisposition. Details ▾Hide ▴

Evidence considered

Frameshift deletion c.5164del creates PTC at codon 1723
well upstream of p.Arg3047
PTC located in exon 34 of 63 coding exons
predicted to trigger NMD
ATM LOF is an established disease mechanism per ClinGen HBOP VCEP v1.5.0
ATM PVS1 decision tree grants PVS1_VeryStrong for null variants with NMD-predicted PTCs

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessmentvcep_atm_pvs1_1_5

PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes), satisfying the ATM VCEP v1.5.0 threshold of <=0.001% for PM2_Supporting. Absence from large population databases supports pathogenicity. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles)
Absent from gnomAD v4.1 (0 alleles)
VCEP threshold for PM2_Supporting: frequency <=0.001% in gnomAD v4

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PM5 SupportingUnder the ATM VCEP v1.5.0, PM5_Supporting is applied to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. This variant creates a PTC at codon 1723, which is well upstream of p.Arg3047 (the most C-terminal pathogenic residue per the VCEP). Details ▾Hide ▴

Evidence considered

Frameshift c.5164del creates PTC at p.Leu1722TrpfsTer2 (aa1723)
PTC is upstream of p.Arg3047
the VCEP-defined C-terminal pathogenic boundary
VCEP PM5 rule: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047'

Sources

cspec ↗vcep_atm_pvs1_1_5

Not met · 2 · evaluated, threshold not reached

BA1 The ATM VCEP v1.5.0 defines BA1 as Grpmax Filtering AF >0.5% in gnomAD v4. This variant is absent from gnomAD v4.1, thus does not satisfy the BA1 threshold. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v4.1
no Grpmax FAF >0.5%

Sources

gnomad_v4 ↗cspec ↗

BS1 The ATM VCEP v1.5.0 defines BS1 as Grpmax Filtering AF >0.05% in gnomAD v4. This variant is absent from gnomAD v4.1, thus does not satisfy the BS1 threshold. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v4.1
no Grpmax FAF >0.05%

Sources

gnomad_v4 ↗cspec ↗

Not assessed · 5 · no assessment recorded

PS3 No variant-specific functional evidence was identified for NM_000051.4:c.5164del. Three publications (PMID:27413114, PMID:30348496, PMID:30553448) were reviewed in full text; none mention this variant. Under the ATM VCEP v1.5.0, PS3 requires demonstration that the variant fails to rescue ATM-specific functional features, but no such data are available. Details ▾Hide ▴

Evidence considered

Three publications reviewed with full-text verification
variant not mentioned in any

Still missing

No functional studies (Kato/Giacomelli
kinase assays
radiosensitivity assays) available for this specific variant

Sources

274131143034849630553448

PS4 The ATM VCEP v1.5.0 specifies PS4 requires case-control studies with p<=0.05 and OR>=2 (or lower 95% CI >=1.5). No such study was identified for this variant. The variant is absent from ClinVar and no case-control data are available. Details ▾Hide ▴

Evidence considered

VCEP defines PS4 as case-control statistical evidence only
No case-control studies identified for c.5164del

Still missing

No case-control or cohort enrichment data available

ATM c.5164del, p.(Leu1722TrpfsTer2)

Variant description:

In plain language

About ATM

How it was classified

Recorded applied criteria

Evidence at a glance

Technical detail

Met · 3

Evidence considered

Sources

Evidence considered

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Evidence considered

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Not met · 2 · evaluated, threshold not reached

Evidence considered

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Evidence considered

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Not assessed · 5 · no assessment recorded

Evidence considered

Still missing

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Evidence considered

Still missing

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Still missing

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Evidence considered

Still missing

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Evidence considered

Still missing

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Identifiers

Gene diagram

By genetic ancestry

gnomAD-Canada

Statements

SpliceAI and Pangolin

Other predictors

How the predictions were used