ATMc.1158delPathogenic

Print report

Variant interpretation report

ATM c.1158del, p.(Lys387ArgfsTer3)

NM_000051.3:c.1158del NP_000042.3:p.(Lys387ArgfsTer3) 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) · 3 supporting (pathogenic)
Expert rules: ClinGen ATM VCEP v1.5.0
Other laboratories (ClinVar): 8 Pathogenic
Pipeline record: 19 May 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000051.3:c.1158del causes an early frameshift, NP_000042.3:p.(Lys387ArgfsTer3), with a premature stop after residue 389. The ATM VCEP PVS1 framework states that loss of function is an established disease mechanism for ATM, that NM_000051.3 exons are constitutive, and that caution is mainly needed for extreme 3' variants; this truncation is far upstream of that region and is consistent with a null allele.
PM2 (supporting): This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 5/1614094 alleles (AF 3.09771e-06, 0.00031%), with highest subpopulation frequency 4.2375e-06 (0.00042%) in European non-Finnish individuals and no homozygotes. These values are below the ATM VCEP PM2_Supporting threshold of 0.001%.
PM5 (supporting): The ATM VCEP repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift creates NP_000042.3:p.(Lys387ArgfsTer3), which is far upstream of p.Arg3047, so PM5_Supporting is met under the gene-specific truncation rule.
PP5 (supporting): Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.

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: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PVS1Very strong

PVS1 · very strong

NM_000051.3:c.1158del causes an early frameshift, NP_000042.3:p.(Lys387ArgfsTer3), with a premature stop after residue 389. The ATM VCEP PVS1 framework states that loss of function is an established disease mechanism for ATM, that NM_000051.3 exons are constitutive, and that caution is mainly needed for extreme 3' variants; this truncation is far upstream of that region and is consistent with a null allele.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 5/1614094 alleles (AF 3.09771e-06, 0.00031%), with highest subpopulation frequency 4.2375e-06 (0.00042%) in European non-Finnish individuals and no homozygotes. These values are below the ATM VCEP PM2_Supporting threshold of 0.001%.

PM5Supporting

PM5 · supporting

The ATM VCEP repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift creates NP_000042.3:p.(Lys387ArgfsTer3), which is far upstream of p.Arg3047, so PM5_Supporting is met under the gene-specific truncation rule.

PP5Supporting

PP5 · supporting

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.

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, PP5 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

5 / 1,614,094 alleles

gnomAD v4.1: 5 / 1,614,094 alleles. Recorded AF 3.09771e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗

SpliceAI score

0.110 maximum delta

Recorded SpliceAI maximum delta score: 0.110. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

8 reported laboratory submissions

8 Pathogenic.

Applied · PP5 → 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: 4 met · 2 not met · 6 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5

Benign

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

Met Not met Not assessed Not applicable

The ATM NM_000051.3:c.1158del (NP_000042.3:p.(Lys387ArgfsTer3)) variant has been reported in ClinVar as pathogenic with expert panel review, and curated cancer knowledgebase review links this exact variant to cancer-related literature.

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 5/1614094 alleles (AF 3.09771e-06; 0.00031%) with no homozygotes, which is below the ATM VCEP PM2_Supporting threshold of 0.001%.

This early frameshift introduces a premature stop after residue 389, and the ATM VCEP framework supports loss of function as an established disease mechanism for ATM; because the truncation is far upstream of the ATM-specific p.Arg3047 cutoff, the evidence supports PVS1 and the ATM-specific PM5_Supporting truncation rule.

Met · 4

PVS1 Very strongNM_000051.3:c.1158del causes an early frameshift, NP_000042.3:p.(Lys387ArgfsTer3), with a premature stop after residue 389. The ATM VCEP PVS1 framework states that loss of function is an established disease mechanism for ATM, that NM_000051.3 exons are constitutive, and that caution is mainly needed for extreme 3' variants; this truncation is far upstream of that region and is consistent with a null allele. Details ▾Hide ▴

Rule

ATM VCEP PVS1 decision tree

Evidence considered

Early frameshift with stop at codon 389
ATM VCEP PVS1 decision tree
ATM loss-of-function disease mechanism established

Sources

cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 5/1614094 alleles (AF 3.09771e-06, 0.00031%), with highest subpopulation frequency 4.2375e-06 (0.00042%) in European non-Finnish individuals and no homozygotes. These values are below the ATM VCEP PM2_Supporting threshold of 0.001%. Details ▾Hide ▴

Rule

ATM PM2_Supporting frequency <=0.001% in gnomAD v4

Evidence considered

gnomAD v2 absence
gnomAD v4 total AF 3.09771e-06
ATM PM2 threshold <=0.001%

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

PM5 SupportingThe ATM VCEP repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift creates NP_000042.3:p.(Lys387ArgfsTer3), which is far upstream of p.Arg3047, so PM5_Supporting is met under the gene-specific truncation rule. Details ▾Hide ▴

Rule

ATM PM5_Supporting for truncating variants upstream of p.Arg3047

Evidence considered

ATM gene-specific PM5 truncation cutoff
Premature stop at residue 389

Sources

cspec ↗pm5_candidates

PP5 SupportingExpert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ATM CSPEC applicability
ClinVar expert panel classification

Sources

cspec ↗clinvar ↗

Not met · 2 · evaluated, threshold not reached

BA1 The gnomAD v4.1 grpmax filtering allele frequency is 1.24e-06 (0.000124%), which is below the ATM BA1 threshold of greater than 0.5%. Details ▾Hide ▴

Rule

ATM BA1 grpmax filtering AF >0.5%

Evidence considered

grpmax FAF 1.24e-06
ATM BA1 threshold >0.5%

Sources

gnomad_v4 ↗cspec ↗

BS1 The highest observed gnomAD v4.1 population frequency is 4.2375e-06 (0.00042%), which is below the ATM BS1 threshold of greater than 0.05%. Details ▾Hide ▴

Rule

ATM BS1 grpmax filtering AF >0.05%

Evidence considered

Highest subpopulation AF 4.2375e-06
ATM BS1 threshold >0.05%

Sources

gnomad_v4 ↗cspec ↗

Not assessed · 6 · no assessment recorded

PS3 Published functional references were identified, but no retrieved evidence documented a variant-specific ATM rescue assay for c.1158del showing failure to rescue an ATM-specific feature under the ATM VCEP PS3 framework. Details ▾Hide ▴

Rule

ATM PS3 requires failure to rescue defined ATM functional readouts

Evidence considered

Functional literature leads identified
No exact variant-specific PS3-qualifying assay retrieved

Still missing

Direct review of any exact-variant functional assay report would be needed to apply PS3.

Sources

oncokb ↗PMID:19147735 ↗PMID:25614872 ↗PMID:27413114 ↗PMID:30348496 ↗PMID:30553448 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951

PS4 This variant has been reported in affected individuals and is classified as pathogenic in ClinVar, but no case-control study, odds ratio, or other quantitative enrichment data meeting the ATM VCEP PS4 threshold were retrieved. Details ▾Hide ▴

Rule

ATM PS4 requires case-control evidence with p<=0.05 and risk estimate threshold

Evidence considered

ClinVar expert panel pathogenic assertion
Primary literature leads without quantitative enrichment data

Still missing

Direct extraction of affected-case counts and any control comparison from primary studies would be needed for PS4.

Sources

clinvar ↗PMID:10234507 ↗PMID:15928302 ↗PMID:19147735 ↗PMID:23807571 ↗PMID:25614872 ↗

PM3 Primary literature linked to this variant suggests possible ataxia-telangiectasia case reports, but no retrieved evidence confirmed the exact number of affected probands, the presence of a second pathogenic ATM variant, or phase information required to assign ATM PM3 points. Details ▾Hide ▴

Rule

ATM PM3 point-based framework

Evidence considered

ClinVar literature leads
ATM PM3/BP2 point framework

Still missing

Need exact proband-level genotype and phase data to score PM3 under the ATM point system.

Sources

clinvar ↗PMID:10234507 ↗PMID:15928302 ↗PMID:19147735 ↗PMID:23807571 ↗PMID:25614872 ↗vcep_atm_pm3_bp2_1_5

PP1 No segregation data were identified that documented this variant tracking with ATM-related disease in the number of affected relatives required by the ATM VCEP PP1 framework. Details ▾Hide ▴

Rule

ATM PP1 uses affected-relative counts for autosomal recessive disease

Evidence considered

Literature leads without extractable segregation counts

Still missing

Pedigree-level segregation data would be needed to assess PP1.

Sources

clinvar ↗PMID:15928302 ↗vcep_atm_pm3_bp2_1_5

BS3 No variant-specific functional study was retrieved showing that c.1158del rescues ATM-specific function or radiosensitivity, so BS3 cannot be applied from the available evidence. Details ▾Hide ▴

Rule

ATM BS3 requires rescue of ATM-specific functional readouts and/or radiosensitivity

Evidence considered

Functional literature leads identified
No BS3-qualifying rescue data retrieved

Still missing

An exact-variant benign functional rescue result would be needed for BS3.

Sources

oncokb ↗PMID:19147735 ↗PMID:25614872 ↗PMID:27413114 ↗PMID:30348496 ↗PMID:30553448 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1

BP2 No retrieved evidence showed this variant in trans with a pathogenic ATM variant in an unaffected individual or other observation meeting the ATM BP2 point framework. Details ▾Hide ▴

Rule

ATM BP2 point-based framework

Evidence considered

ClinVar literature leads
ATM PM3/BP2 point framework

Still missing

Exact phase and phenotype data would be needed to score BP2.

Sources

clinvar ↗PMID:10234507 ↗PMID:15928302 ↗vcep_atm_pm3_bp2_1_5

Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 is a same-amino-acid or matched splice-event rule. This variant is a frameshift deletion, so PS1 does not apply. Details ▾Hide ▴

Rule

ATM PS1 splicing table applies to missense or matched splice-event comparators

Evidence considered

Frameshift consequence

Sources

cspec ↗vcep_atm_ps1_1_5

PS2 VCEPThe ATM VCEP framework does not apply PS2 for this gene-disease context. Details ▾Hide ▴

Evidence considered

ATM CSPEC applicability