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ATMc.4818dupPathogenic
Print report
Variant interpretation report

ATM c.4818dup, p.(Pro1607SerfsTer6)

NM_000051.3:c.4818dup NP_000042.3:p.(Pro1607SerfsTer6) 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.

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

Frameshift variant NM_000051.3:c.4818dup (p.Pro1607SerfsTer6) creates a premature termination codon at residue 1612 in ATM, a gene where loss of function is an established mechanism for ataxia-telangiectasia and hereditary breast/ovarian/pancreatic cancer. The PTC is NMD-competent and lies well upstream of the C-terminal boundary (p.Arg3047) specified by the ATM VCEP v1.5.0 PVS1 decision tree. PVS1_VeryStrong applied per ClinGen HBOP VCEP specifications.

PM2Supporting
PM2 · supporting

NM_000051.3:c.4818dupT is absent from gnomAD v4.1 (0 alleles, AF=0), satisfying the ATM VCEP PM2_Supporting threshold of ≤0.001% population frequency.

PM5Supporting
PM5 · supporting

This frameshift variant creates a premature termination codon at p.Pro1607SerfsTer6 (PTC at codon 1612), which lies upstream of p.Arg3047, satisfying the ATM VCEP v1.5.0 PM5_Supporting rule for frameshifting/truncating variants with PTCs 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.

SpliceAI score
0.240 maximum delta

Recorded SpliceAI maximum delta score: 0.240. 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
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000051.3:c.4818dupT (p.Pro1607SerfsTer6) is a frameshift duplication in exon 32 of ATM predicted to cause nonsense-mediated decay and complete loss of ATM protein function (PVS1_VeryStrong).

The variant is absent from gnomAD v4.1 population database (0/1,614,094 alleles), meeting the ATM VCEP PM2_Supporting threshold of ≤0.001% allele frequency.

The premature termination codon at p.Pro1607SerfsTer6 lies upstream of p.Arg3047, satisfying the ATM VCEP PM5_Supporting rule for frameshifting variants with PTCs upstream of this C-terminal boundary.

No variant-specific functional studies, case-control data, co-segregation data, or co-occurrence data were identified for this variant in the literature screened (PMID:27413114, PMID:30348496, PMID:30553448).

The variant is not present in ClinVar and has not been reported in COSMIC or in statistically significant mutational hotspots.

Met · 3

PVS1 Very strongFrameshift variant NM_000051.3:c.4818dup (p.Pro1607SerfsTer6) creates a premature termination codon at residue 1612 in ATM, a gene where loss of function is an established mechanism for ataxia-telangiectasia and hereditary breast/ovarian/pancreatic cancer. The PTC is NMD-competent and lies well upstream of the C-terminal boundary (p.Arg3047) specified by the ATM VCEP v1.5.0 PVS1 decision tree. PVS1_VeryStrong applied per ClinGen HBOP VCEP specifications. Details ▾Hide ▴
Evidence considered
  • NM_000051.3:c.4818dup is a frameshift duplication in exon 32 of 63 coding exons
  • Predicted protein consequence: NP_000042.3:p.(Pro1607SerfsTer6)
  • PTC at codon 1612 of 3056
  • ATM loss of function is an established disease mechanism for A-T (autosomal recessive) and HBOP cancer predisposition (autosomal dominant)
  • ATM VCEP v1.5.0 PVS1 decision tree supports PVS1_VeryStrong for NMD-competent frameshift variants upstream of p.Arg3047
Sources
cspec ↗pvs1_generic_framework ↗
PM2 SupportingNM_000051.3:c.4818dupT is absent from gnomAD v4.1 (0 alleles, AF=0), satisfying the ATM VCEP PM2_Supporting threshold of ≤0.001% population frequency. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0 alleles
  • allele frequency = 0
  • gnomAD v2.1: absent
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v4 ↗
PM5 SupportingThis frameshift variant creates a premature termination codon at p.Pro1607SerfsTer6 (PTC at codon 1612), which lies upstream of p.Arg3047, satisfying the ATM VCEP v1.5.0 PM5_Supporting rule for frameshifting/truncating variants with PTCs upstream of p.Arg3047. Details ▾Hide ▴
Evidence considered
  • Predicted protein: NP_000042.3:p.(Pro1607SerfsTer6)
  • PTC at codon 1612
  • p.Arg3047 is the VCEP-specified C-terminal cutoff for PM5 application
  • PTC at 1612 is well upstream of p.Arg3047
Sources
cspec ↗

Not met · 2 · evaluated, threshold not reached

BA1 NM_000051.3:c.4818dupT is absent from gnomAD v4.1 (0 alleles). Does not meet the ATM VCEP BA1 threshold of grpmax filtering allele frequency >0.5%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0 alleles
  • grpmax FAF = 0
Sources
gnomad_v4 ↗
BS1 NM_000051.3:c.4818dupT is absent from gnomAD v4.1 (0 alleles). Does not meet the ATM VCEP BS1 threshold of grpmax filtering allele frequency >0.05%. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 0 alleles
  • grpmax FAF = 0
Sources
gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS3 No variant-specific functional studies were identified for NM_000051.3:c.4818dupT. Three papers retrieved through literature screening (PMID:27413114, PMID:30348496, PMID:30553448) discuss ATM gene-level biology and functional pathways but do not mention or study this specific variant. Details ▾Hide ▴
Evidence considered
  • PMID:27413114 — review of ATM mutations in cancer
  • no variant-specific data
  • PMID:30348496 — mouse Atm kinase-dead model
  • no human variant c.4818dup studied
  • PMID:30553448 — Rac1/ROS in ATM-deficient cells
Still missing
  • No variant-specific functional assay data (kinase activity
  • radiosensitivity rescue
  • or ATM substrate phosphorylation) available for p.Pro1607SerfsTer6
PS4 No case-control study data are available for NM_000051.3:c.4818dupT. ATM VCEP v1.5.0 requires case-control studies with p-value ≤0.05 AND (OR ≥2 OR lower 95% CI ≥1.5) for PS4_Strong. Details ▾Hide ▴
Still missing
  • No case-control association data available
PP1 No co-segregation data are available for NM_000051.3:c.4818dupT. ATM VCEP v1.5.0 PP1 applies to autosomal recessive A-T (segregation in affected relatives); no family studies identified. Details ▾Hide ▴
Still missing
  • No co-segregation data in A-T families
BS3 No variant-specific functional rescue data are available for NM_000051.3:c.4818dupT. ATM VCEP v1.5.0 BS3 requires evidence that a variant rescues ATM-specific features (e.g., phosphorylation of ATM-specific targets) and/or radiosensitivity; no such studies identified. Details ▾Hide ▴
Still missing
  • No variant-specific functional rescue assay data (kinase activity rescue
  • radiosensitivity rescue)
BP2 No co-occurrence data in trans with a known pathogenic ATM variant are available for NM_000051.3:c.4818dupT. ATM VCEP BP2 requires proband-level data with points assigned per the PM3/BP2 table; no such data identified. Details ▾Hide ▴
Still missing
  • No co-occurrence data in trans with a second pathogenic ATM variant
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 under ATM VCEP v1.5.0 applies to missense changes or splicing variants with a same-nucleotide comparator. This is a frameshift duplication variant. Details ▾Hide ▴
Sources
cspec ↗
PS2 VCEPPS2 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
PM1 VCEPPM1 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
PM4 N/APM4 under ATM VCEP v1.5.0 is restricted to stop-loss variants. NM_000051.3:c.4818dupT is a frameshift duplication, not a stop-loss variant. Details ▾Hide ▴
Sources
cspec ↗
PM6 VCEPPM6 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPPP2 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
PP3 N/APP3 under ATM VCEP v1.5.0 applies to missense variants (REVEL >0.7333) or splicing/silent/intronic variants (SpliceAI ≥0.2). NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. Details ▾Hide ▴
Sources
cspec ↗
PP4 VCEPPP4 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPPP5 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
BS2 VCEPBS2 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
BS4 VCEPBS4 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPBP1 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
BP3 VCEPBP3 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
BP4 N/ABP4 under ATM VCEP v1.5.0 applies to missense variants (REVEL ≤0.249) or splicing variants (SpliceAI ≤0.1). NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. Details ▾Hide ▴
Sources
cspec ↗
BP5 VCEPBP5 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
BP6 VCEPBP6 is marked Not Applicable by the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 under ATM VCEP v1.5.0 applies to synonymous and deep intronic variants. NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. Details ▾Hide ▴
Sources
cspec ↗
PS5 N/APS5 is not defined in the ATM VCEP v1.5.0 criteria specifications. This criterion is excluded by the VCEP framework. Details ▾Hide ▴
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.3
Coding (HGVS c.)
NM_000051.3:c.4818dup
Protein (HGVS p.)
NP_000042.3:p.(Pro1607SerfsTer6)
GRCh38
chr11:108294966 C>CT
GRCh37
chr11:108165693 C>CT

Gene diagram

Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.3. Select a row to find it on the plot.

ATMNM_000051.3
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 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -39 bp
0.140
SpliceAI acceptor gainat +14 bp
0.000
SpliceAI donor lossat +93 bp
0.240
SpliceAI donor gainat -19 bp
0.040
Pangolin splice lossmagnitude shown
-0.210
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/APP3 under ATM VCEP v1.5.0 applies to missense variants (REVEL >0.7333) or splicing/silent/intronic variants (SpliceAI ≥0.2). NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. Details ▾Hide ▴
Sources
cspec ↗
BP4 N/ABP4 under ATM VCEP v1.5.0 applies to missense variants (REVEL ≤0.249) or splicing variants (SpliceAI ≤0.1). NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 under ATM VCEP v1.5.0 applies to synonymous and deep intronic variants. NM_000051.3:c.4818dupT is a frameshift duplication and does not fall under these categories. Details ▾Hide ▴
Sources
cspec ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.24).

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.
    Review article discussing the spectrum of ATM mutations in cancer, ATM protein structure and function, and therapeutic strategies targeting ATM-deficient cancers. NM_000051.3:c.4818dupT was not identified in this paper.
    Does not name this variant
    PMID 27413114 ↗
  • Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
    Mouse study investigating the effects of conditional expression of kinase-dead Atm versus Atm loss in the cerebellum. Used genetically engineered Atm knockout and kinase-dead mouse alleles; no human variant NM_000051.3:c.4818dupT was studied or mentioned.
    Does not name this variant
    PMID 30348496 ↗
  • Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
    Cell biology study demonstrating that loss of ATM kinase activity elevates ROS levels leading to Rac1 activation and increased cell migration. Used ATM-/- human fibroblasts and pharmacological ATM inhibition; NM_000051.3:c.4818dupT was not studied or mentioned.
    Does not name this variant
    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 Recorded maximum delta 0.240 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.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.24).

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.