ATMc.8052_8055delPathogenic

Print report

Variant interpretation report

ATM c.8052_8055del, p.(Gln2684HisfsTer8)

NM_000051.4:c.8052_8055del NP_000042.3:p.(Gln2684HisfsTer8) 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

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): This 4-bp deletion causes a frameshift, p.Gln2684HisfsTer8 (p.Q2684Hfs*8), in exon 55 of ATM. In the ATM VCEP framework, loss of function is an established disease mechanism, the reference transcript exons are considered constitutive, and this premature stop is well upstream of the transcript end rather than at the extreme 3′ end, supporting PVS1 at very strong strength.
PM2 (supporting): This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. An observed frequency of 0 is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4, so PM2_Supporting is met.
PM5 (supporting): ATM repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a premature stop at p.Gln2691, which is upstream of p.Arg3047, so ATM-specific PM5_Supporting is met; classic same-residue missense comparator logic is not required for this gene-specific rule.

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

This 4-bp deletion causes a frameshift, p.Gln2684HisfsTer8 (p.Q2684Hfs*8), in exon 55 of ATM. In the ATM VCEP framework, loss of function is an established disease mechanism, the reference transcript exons are considered constitutive, and this premature stop is well upstream of the transcript end rather than at the extreme 3′ end, supporting PVS1 at very strong strength.

PM2Supporting

PM2 · supporting

This variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. An observed frequency of 0 is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4, so PM2_Supporting is met.

PM5Supporting

PM5 · supporting

ATM repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a premature stop at p.Gln2691, which is upstream of p.Arg3047, so ATM-specific PM5_Supporting is met; classic same-residue missense comparator logic is not required for this gene-specific rule.

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, PM5 supporting, PM2 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 ↗

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

Not assessed

No COSMIC evidence statement is recorded in this case.

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 · 3 not met · 5 not assessed · 17 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 c.8052_8055del (p.Gln2684HisfsTer8; p.Q2684Hfs*8) variant has not been observed in somatic cancers in COSMIC and is reported in ClinVar as pathogenic.

This variant is absent from gnomAD v2.1 and v4.1, which is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4 and does not meet the BS1 (>0.05%) or BA1 (>0.5%) population thresholds.

This 4-bp deletion causes a frameshift in exon 55 with a premature stop codon, and under the ATM VCEP framework that supports PVS1 at very strong strength; because the predicted stop is upstream of p.Arg3047, it also meets the ATM-specific truncation-based PM5 rule.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, and the ATM PP3/BP4 computational rules are not applied to this exonic frameshift variant class.

Met · 3

PVS1 Very strongThis 4-bp deletion causes a frameshift, p.Gln2684HisfsTer8 (p.Q2684Hfs*8), in exon 55 of ATM. In the ATM VCEP framework, loss of function is an established disease mechanism, the reference transcript exons are considered constitutive, and this premature stop is well upstream of the transcript end rather than at the extreme 3′ end, supporting PVS1 at very strong strength. Details ▾Hide ▴

Rule

Use ATM PVS1 Decision Tree.

Evidence considered

Frameshift consequence p.Gln2684HisfsTer8 / p.Q2684Hfs*8
Variant maps to exon 55
ATM VCEP includes gene-specific PVS1 guidance

Sources

cspec ↗vcep_atm_pvs1_1_5pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis variant is absent from gnomAD v4.1 and absent from gnomAD v2.1. An observed frequency of 0 is below the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4, so PM2_Supporting is met. Details ▾Hide ▴

Rule

Frequency ≤0.001% in gnomAD v4 dataset. If n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply.

Evidence considered

Absent from gnomAD v4.1
Absent from gnomAD v2.1

Sources

cspec ↗gnomad_v4 ↗gnomad_v2 ↗

PM5 SupportingATM repurposes PM5 for truncating variants with premature termination codons upstream of p.Arg3047. This frameshift introduces a premature stop at p.Gln2691, which is upstream of p.Arg3047, so ATM-specific PM5_Supporting is met; classic same-residue missense comparator logic is not required for this gene-specific rule. Details ▾Hide ▴

Rule

Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.

Evidence considered

ATM-specific PM5 truncation-cutoff rule
Predicted stop upstream of p.Arg3047

Sources

cspec ↗pm5_candidates

Not met · 3 · evaluated, threshold not reached

PS4 This variant has been reported in ClinVar and cited literature, but no case-control study or exact-variant enrichment analysis was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥2, or a lower 95% confidence interval ≥1.5. Therefore PS4 is not met. Details ▾Hide ▴

Rule

Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).

Evidence considered

ClinVar pathogenic submissions
Published case reports cited by ClinVar

Still missing

No qualifying case-control or enrichment dataset for this exact variant was identified.

Sources

cspec ↗clinvar ↗PMID:23807571 ↗PMID:25614872 ↗

BA1 This variant is absent from gnomAD v4.1. An observed frequency of 0 is below the ATM BA1 threshold of >0.5%, so BA1 is not met. Details ▾Hide ▴

Rule

Grpmax Filtering AF >.5% in gnomAD v4 dataset

Evidence considered

Absent from gnomAD v4.1

Sources

cspec ↗gnomad_v4 ↗

BS1 This variant is absent from gnomAD v4.1. An observed frequency of 0 is below the ATM BS1 threshold of >0.05%, so BS1 is not met. Details ▾Hide ▴

Rule

Grpmax Filtering AF >.05% in gnomAD v4 dataset

Evidence considered

Absent from gnomAD v4.1

Sources

cspec ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS3 Available functional publications reviewed in curated sources describe ATM loss-of-function biology or assays of other ATM alterations, but no direct assay of this specific variant was identified showing failure to rescue ATM-specific function and radiosensitivity as required by the ATM framework. Therefore PS3 is not assigned. Details ▾Hide ▴

Rule

Use when a variant fails to rescue both an ATM specific feature AND radiosensitivity, or supporting if it fails to rescue an ATM specific feature only.

Evidence considered

Curated functional literature review
No direct assay of c.8052_8055del identified

Still missing

No variant-specific functional rescue study was identified.

Sources

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

PM3 No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an affected individual was identified, so PM3 cannot be assigned from the available evidence. Details ▾Hide ▴

Rule

See ATM PM3/BP2 table for approach to assign points per proband.

Evidence considered

ATM PM3/BP2 point-based framework reviewed
ClinVar record reviewed

Still missing

No phased biallelic case data were identified for this variant.

Sources

vcep_atm_pm3_bp2_1_5clinvar ↗

PP1 No segregation data were identified for this variant in affected relatives, so PP1 cannot be assigned. Details ▾Hide ▴

Rule

AR Condition: Segregation in affected relatives.

Evidence considered

No qualifying segregation data identified

Still missing

No family segregation evidence was identified.

BS3 No direct assay of this specific variant was identified showing rescue of ATM-specific function or radiosensitivity. Therefore BS3 is not assigned. Details ▾Hide ▴

Rule

Use when a variant rescues ATM-specific function and/or radiosensitivity.

Evidence considered

Curated functional literature review
No direct rescue assay for c.8052_8055del identified

Still missing

No variant-specific rescue assay was identified.

Sources

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

BP2 No evidence was identified showing this variant in trans with a pathogenic ATM variant in an unaffected individual, with phase unknown in an unaffected individual, or as a qualifying homozygous finding under the ATM BP2 framework. Therefore BP2 is not assigned. Details ▾Hide ▴

Rule

See ATM PM3/BP2 table for approach to assign points per proband.

Evidence considered

ATM PM3/BP2 point-based framework reviewed

Still missing

No qualifying unaffected co-occurrence data were identified.

Sources

vcep_atm_pm3_bp2_1_5

Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/AThis variant is a frameshift deletion and does not meet the ATM PS1 framework, which is specified for missense substitutions or defined splicing comparators. Details ▾Hide ▴

Rule

Use for missense changes or defined PS1 splicing comparators.

Evidence considered

Variant class is frameshift

Sources

cspec ↗vcep_atm_ps1_1_5

PS2 N/AATM PS2 is designated not applicable in the gene-specific framework, so it is not used for this variant. Details ▾Hide ▴

Evidence considered

ATM VCEP applicability statement