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ATMc.7628dupPathogenic
Print report
Variant interpretation report

ATM c.7628dup, p.(Asn2543LysfsTer5)

NM_000051.4:c.7628dup NP_000042.3:p.(Asn2543LysfsTer5) Frameshift · exon 51 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

ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.

NCBI Gene ↗ OncoKB ↗
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. 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

Met: one-base frameshift creates premature stop codon p.(Asn2543LysfsTer5) predicted to trigger nonsense-mediated decay, truncating about 510 residues.

PM2Supporting
PM2 · supporting

Met (supporting): absent from gnomAD v4.1, below the <=0.001% frequency threshold.

PM5Supporting
PM5 · supporting

Met (supporting): the premature stop at approximately p.2547 lies upstream of the p.Arg3047 ATM truncation cutoff.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: ATM VCEP v1.5 Rule4 is met by one very strong criterion (PVS1) and two supporting criteria (PM2, PM5).

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
0.028 maximum delta

Recorded SpliceAI maximum delta score: 0.028. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Pathogenic. ClinVar API review status: criteria provided, single submitter.

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, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 2 not met · 6 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

Within this group, ATM c.7628dup meets PVS1 at Very Strong strength because it is an NMD-prone frameshift null variant in a gene with an established loss-of-function disease mechanism under the ATM VCEP specification.

PM4 and BP3 are not applicable under the ATM VCEP v1.5 rules for this variant.

The variant NM_000051.4:c.7628dup in ATM is a frameshift, NP_000042.3:p.(Asn2543LysfsTer5), adjudicated under the ClinGen HBOP ATM VCEP v1.5 framework.

PM5 is met at Supporting strength under the ATM-specific truncation-cutoff rule because the premature termination is upstream of p.Arg3047.

PS1, PM1, PP2, and BP1 are not applicable under the governing ATM VCEP specification and/or the variant class.

The ClinGen HBOP ATM VCEP version 1.5 governs this assessment because an applicable gene-specific specification is present.

The variant is absent from gnomAD v4.1, supporting PM2 at Supporting strength while remaining below the BA1 and BS1 thresholds.

BS2 is not applicable under the ATM VCEP specification.

Met · 3

PVS1 Very strongMet: one-base frameshift creates premature stop codon p.(Asn2543LysfsTer5) predicted to trigger nonsense-mediated decay, truncating about 510 residues. Details ▾Hide ▴
Reasoning

ATM c.7628dup is a one-base frameshift on the MANE Select transcript NM_000051.4, predicted to cause p.(Asn2543LysfsTer5). The premature termination occurs at predicted residue 2548, truncating the 3057-residue reference protein by approximately 510 residues. The affected nucleotide is in exon 51 and is followed by multiple coding exons, so the premature termination codon is NMD-prone rather than in the terminal exon or an extreme 3′ escape region. The ATM VCEP PVS1 guide explicitly covers frameshift null variants, treats exons of its default transcript as constitutive, and establishes loss of function as a disease mechanism; full-strength PVS1 is therefore appropriate.

Rule
ATM VCEP v1.5 PVS1 decision guide for frameshift null variants in ATM; PVS1 (Very Strong).
Evidence considered
  • Case normalization identifies NM_000051.4:c.7628dup as NP_000042.3:p.(Asn2543LysfsTer5), with the reference protein ending at residue 3057 and the predicted frameshift product ending at residue 2547 before the stop.
  • Transcript exon coordinates place c.7628 in exon 51; multiple coding exons remain downstream, supporting nonsense-mediated decay of the premature-termination transcript.
  • The ATM VCEP v1.5 PVS1 guide defines frameshift variants as null-variant candidates in ATM, states that loss of function is a known disease mechanism, and considers all exons of its default transcript constitutive; its caution concerns only loss-of-function variants at the extreme 3′ end or splice variants with in-frame exon skipping, neither of which describes this variant.
Sources
cspec ↗vcep_atm_pvs1_1_5
PM2 SupportingMet (supporting): absent from gnomAD v4.1, below the <=0.001% frequency threshold. Details ▾Hide ▴
Reasoning

PM2_Supporting is met under the ATM VCEP version 1.5. The variant is absent from gnomAD v4.1, satisfying the specified frequency threshold of <=0.001%. It is also absent from gnomAD v2.1 and gnomAD-Canada v1.0, with no ancestry-specific frequency or homozygote signal reported in the case bundle.

Rule
Frequency <=0.001% in the gnomAD v4 dataset; if n=1 in a single subpopulation, that is sufficient for PM2_Supporting.
Evidence considered
  • The ClinGen HBOP ATM VCEP version 1.5 PM2 rule applies at supporting strength when frequency is <=0.001% in gnomAD v4; n=1 in a single subpopulation is also sufficient for PM2_Supporting.
  • gnomAD v4.1 reports the variant as absent.
  • The variant is additionally reported absent from gnomAD v2.1 and gnomAD-Canada v1.0; no homozygote or ancestry-specific frequency is reported.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
PM5 SupportingMet (supporting): the premature stop at approximately p.2547 lies upstream of the p.Arg3047 ATM truncation cutoff. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 PM5 rule applies Supporting-strength PM5 to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. NM_000051.4:c.7628dup produces p.(Asn2543LysfsTer5), a frameshift with a premature termination at approximately p.2547, which is upstream of p.Arg3047. The rule is therefore satisfied at Supporting strength; this is the ATM-specific truncation-cutoff PM5 pathway, not classic same-residue missense PM5.

Rule
ATM_VCEP_v1.5_PM5_truncation_cutoff
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 PM5 rule: apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047; the rule lists Supporting as the applicable strength.
  • Case normalization identifies NM_000051.4:c.7628dup as NP_000042.3:p.(Asn2543LysfsTer5), placing the premature termination before p.Arg3047.
  • pm5_candidates.json identifies the governing ATM PM5 mode as truncation_cutoff_gene_specific and states that classic same-residue missense searching is not eligible for this non-missense variant.
Sources
cspec ↗pm5_candidates

Not met · 2 · evaluated, threshold not reached

BA1 Not met: absent from gnomAD v4.1, far below the >0.5% filtering allele frequency threshold. Details ▾Hide ▴
Reasoning

BA1 is not met. The ATM VCEP version 1.5 requires a gnomAD v4 grpmax filtering allele frequency greater than 0.5% for BA1. The variant NM_000051.4:c.7628dup is absent from gnomAD v4.1, so no population frequency approaches the stand-alone benign threshold.

Rule
Grpmax filtering allele frequency >0.5% in the gnomAD v4 dataset.
Evidence considered
  • The ClinGen HBOP ATM VCEP version 1.5 BA1 rule is grpmax filtering AF >0.5% in gnomAD v4.
  • gnomAD v4.1 reports the variant as absent; therefore no grpmax filtering AF is available above the BA1 threshold.
Sources
cspec ↗gnomad_v4 ↗
BS1 Not met: absent from gnomAD v4.1, below the >0.05% disease-compatible frequency threshold. Details ▾Hide ▴
Reasoning

BS1 is not met. The ATM VCEP version 1.5 requires a gnomAD v4 grpmax filtering allele frequency greater than 0.05% for BS1. The variant is absent from gnomAD v4.1, so the observed frequency does not exceed the disease-compatible threshold.

Rule
Grpmax filtering allele frequency >0.05% in the gnomAD v4 dataset.
Evidence considered
  • The ClinGen HBOP ATM VCEP version 1.5 BS1 rule is grpmax filtering AF >0.05% in gnomAD v4.
  • gnomAD v4.1 reports the variant as absent; therefore no grpmax filtering AF exceeds the BS1 threshold.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 6 · no assessment recorded

PS3 Not assessed: no variant-specific validated functional assay result was available. Details ▾Hide ▴
Reasoning

No variant-specific validated functional assay result was identified for ATM NM_000051.4:c.7628dupA (p.Asn2543LysfsTer5). The ATM VCEP v1.5 specification requires direct confirmation that the variant was tested and that an approved ATM-specific functional readout is abnormal; the available extracted papers either do not mention this variant or provide only sequencing, review, or model-system context. The variant cannot be assigned PS3 from the VCEP assay-calibration table alone.

Rule
ATM VCEP v1.5 PS3: do not use as strong; use moderate when the variant fails to rescue both an ATM-specific feature and radiosensitivity; use supporting when it fails to rescue an ATM-specific feature only; do not use for radiosensitivity-only evidence.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies that PS3 should not be used as strong; supporting strength is for failure to rescue an ATM-specific feature, and moderate strength requires failure to rescue both an ATM-specific feature and radiosensitivity. Radiosensitivity alone is not sufficient.
  • The VCEP-approved assay calibration table describes ATM kinase-activity assays using ATM-null lymphoblastoid cells, wild-type and null/empty-vector controls, and phosphorylation of ATM substrates, but explicitly does not report which variants were tested; the current variant must be confirmed in the cited primary paper before applying PS3.
  • The extracted full-text review for PMID:27413114 searched for c.7628dup and p.(N2543Kfs*5) and found neither; it provides general ATM biology and states that functional impact of individual mutations is not established.
  • The extracted full text for PMID:30348496 searched for c.7628dup and p.(N2543Kfs*5) and found neither; it evaluates conditional Atm-loss and kinase-dead mouse models rather than this variant.
  • The extracted full text for PMID:23807571 searched for c.7628dup and p.(N2543Kfs*5) and found neither; it reports sequencing/MLPA of Chinese ataxia-telangiectasia patients without a variant-specific functional result for this variant.
  • The extracted full text for PMID:25614872 searched for c.7628dup and p.(N2543Kfs*5) and found neither; it reports molecular analysis of Polish ataxia-telangiectasia patients without a variant-specific functional assay result.
Still missing
  • A primary publication or dataset directly testing c.7628dupA in an ATM-specific functional assay is not available in the reviewed evidence.
  • No variant-specific ATM substrate-phosphorylation result or combined validated radiosensitivity result with assay controls was identified.
  • The VCEP-calibrated PS3 strength cannot be assigned without a directly observed variant result and comparison with appropriate normal and abnormal controls.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1PMID:27413114 ↗PMID:30348496 ↗PMID:23807571 ↗PMID:25614872 ↗
PS4 Not assessed: no case-control study met the required threshold (p-value <=0.05 and odds/hazard/relative risk >=2). Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP specification requires a case-control study with p-value ≤0.05 and an odds ratio, hazard ratio, or relative risk ≥2 (or lower 95% CI ≥1.5). No such exact-variant case-control enrichment data are present.

Rule
ATM HBOP VCEP v1.5: Case-control studies; p-value ≤0.05 AND (odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).
Evidence considered
  • The governing ATM HBOP VCEP v1.5 PS4 rule requires case-control evidence with p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5.
  • The reviewed full-text extractions for PMID:23807571, PMID:25614872, and PMID:24418350 state that c.7628dup / p.(N2543Kfs*5) was not mentioned; none supplies a case-control estimate for this variant.
Still missing
  • A case-control study reporting exact-variant counts and an effect estimate with confidence interval or p-value is required.
Sources
cspec ↗PMID:23807571 ↗PMID:25614872 ↗PMID:24418350 ↗
PM3 Not assessed: no affected proband, second variant, or trans-phase observation was available to assign points. Details ▾Hide ▴
Reasoning

The applicable ClinGen HBOP ATM VCEP v1.5 PM3/BP2 specification uses points for unrelated patients with ataxia-telangiectasia, weighted by phenotype confidence and whether the variant is confirmed in trans with a VCEP-classified pathogenic/likely pathogenic ATM variant. The bundle contains no affected-proband observation for NM_000051.4:c.7628dup, no second ATM variant, and no phase or parental testing. ClinVar's single-submitter Pathogenic classification cannot be used to infer PM3, and the reviewed papers do not explicitly mention this variant or provide a variant-specific phase observation. Therefore no PM3 points can be assigned.

Rule
ATM VCEP v1.5 PM3: score unrelated A-T probands according to phenotype confidence and allelic phase; PM3 Supporting = 1 point, Moderate = 2 points, Strong = 4 points, Very Strong = 8 points.
Evidence considered
  • The ATM VCEP v1.5 PM3 table assigns 4.0 points for a confident A-T phenotype with the variant confirmed in trans with a pathogenic/likely pathogenic variant, 2.0 points when phase is unknown, 1.0 point when the second variant is unidentified or a VUS, and 2.0 points for a homozygous affected individual, with a maximum of two homozygous individuals; 1, 2, 4, and 8 points correspond to PM3 Supporting, Moderate, Strong, and Very Strong, respectively.
  • The case bundle reports ClinVar variation 4806906 as Pathogenic from one single-submitter laboratory, but it provides no affected-proband, second-allele, parental, or phase information; the classification itself was not used as PM3 evidence.
  • The extracted findings for PMID:23807571 and PMID:25614872 describe A-T cohorts and truncating ATM variants generally, but explicitly do not mention c.7628dup or p.(Asn2543LysfsTer5), so they provide no variant-specific PM3 observation.
Still missing
  • Affected-proband records for NM_000051.4:c.7628dup with an A-T phenotype are not available.
  • A second ATM variant classified under the ATM VCEP specification and its phase relative to c.7628dup are not available.
  • Parental testing or other evidence establishing trans, cis, homozygous, or phase-unknown status is not available.
Sources
vcep_atm_pm3_bp2_1_5clinvar ↗PMID:23807571 ↗PMID:25614872 ↗
PP1 Not assessed: no affected relatives, pedigree genotypes, or phase information was available for segregation analysis. Details ▾Hide ▴
Reasoning

PP1 is applicable for the autosomal-recessive ataxia-telangiectasia context under the ATM VCEP, with Supporting strength for segregation in one affected relative, Moderate for two, and Strong for at least three. However, the case bundle contains no identified affected relatives, pedigree, family genotypes, phase information, or meiosis count for NM_000051.4:c.7628dup. The reviewed exact-variant literature extraction also reports no variant-specific segregation findings. Therefore, PP1 cannot be assigned.

Rule
ATM VCEP v1.5 PP1: AR condition; Supporting for 1 affected relative, Moderate for 2, Strong for >=3; affected relatives must have both variants identified in the proband.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies for autosomal recessive disease: PP1 Supporting for segregation in one affected relative, Moderate for two affected relatives, and Strong for at least three affected relatives; affected relatives must have both variants identified in the proband.
  • The case bundle provides no affected-relative segregation data, family genotypes, pedigree, phase, or meiosis count for this variant.
  • The pre-computed extraction for PMID:25614872 states that the paper does not explicitly mention ATM c.7628dup or p.(N2543Kfs*5) and reports no variant-specific functional or segregation findings for c.7628dup.
Still missing
  • Affected-relative count is not reported.
  • No familial variant testing results or segregation direction are reported.
  • No pedigree, phase information, or informative meioses are reported.
Sources
cspec ↗PMID:25614872 ↗
BS3 Not assessed: no variant-specific functional assay demonstrating normal ATM function was available. Details ▾Hide ▴
Reasoning

No variant-specific validated functional assay demonstrating normal ATM function was identified for ATM NM_000051.4:c.7628dupA (p.Asn2543LysfsTer5). The ATM VCEP v1.5 specification requires direct assay evidence: supporting strength when the variant rescues either an ATM-specific feature or radiosensitivity, and moderate strength when it rescues both. General ATM biology, model-system results, and the VCEP assay-methodology table do not establish a benign functional result for this variant.

Rule
ATM VCEP v1.5 BS3: use moderate when the variant rescues both an ATM-specific feature and radiosensitivity; use supporting when it rescues either an ATM-specific feature or radiosensitivity.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies BS3 moderate when a variant rescues both an ATM-specific feature and radiosensitivity, and BS3 supporting when it rescues either an ATM-specific feature or radiosensitivity.
  • The VCEP-approved assay calibration table provides methodology and control expectations for ATM kinase activity and radiosensitivity assays but is not a per-variant results table; it cannot support BS3 for c.7628dupA without confirmation that the variant was tested and showed a normal/rescue result.
  • The extracted full-text review for PMID:27413114 searched for c.7628dup and p.(N2543Kfs*5) and found neither and specifically notes that the functional impact of individual mutations is not established.
  • The extracted full text for PMID:30348496 searched for c.7628dup and p.(N2543Kfs*5) and found neither and studied conditional Atm-loss and kinase-dead mouse models, not benign function of this variant.
  • The extracted full text for PMID:23807571 searched for c.7628dup and p.(N2543Kfs*5) and found neither and reported molecular testing without a variant-specific functional rescue result.
  • The extracted full text for PMID:25614872 searched for c.7628dup and p.(N2543Kfs*5) and found neither and reported molecular testing without a variant-specific functional assay result.
Still missing
  • A primary publication or dataset directly testing c.7628dupA in a validated ATM functional assay is not available in the reviewed evidence.
  • No variant-specific normal ATM substrate-phosphorylation result, radiosensitivity result, or assay-control-supported rescue result was identified.
  • The VCEP-calibrated BS3 strength cannot be assigned without a directly observed variant result and appropriate assay controls.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1PMID:27413114 ↗PMID:30348496 ↗PMID:23807571 ↗PMID:25614872 ↗
BP2 Not assessed: no unaffected co-occurrence, second variant, or phase information was available. Details ▾Hide ▴
Reasoning

The applicable ClinGen HBOP ATM VCEP v1.5 BP2 specification uses negative points for unaffected, non-A-T individuals carrying the variant with a VCEP-classified pathogenic/likely pathogenic ATM variant in trans, with separate handling for confirmed trans, phase unknown, and homozygous observations; the general BP2 cis path is also relevant when a variant is observed in cis with a pathogenic variant. The bundle contains no unaffected adult co-occurrence, no second pathogenic/likely pathogenic ATM variant, and no phase information. The reviewed papers do not explicitly mention this variant or provide a cis/trans observation. Therefore BP2 cannot be assigned.

Rule
ATM VCEP v1.5 BP2: evaluate unaffected non-A-T individuals carrying the variant with a VCEP-classified pathogenic/likely pathogenic ATM variant using phase-specific negative points; BP2 Supporting = -1 point, Moderate = -2 points, Strong = ≤-4 points.
Evidence considered
  • The ATM VCEP v1.5 BP2 table assigns -4.0 points for an unaffected individual with a pathogenic/likely pathogenic variant confirmed in trans, -2.0 points when phase is unknown, and -2.0 or -1.0 points for homozygous observations depending on laboratory versus database setting; BP2 Supporting = -1 point, Moderate = -2 points, and Strong = ≤-4 points.
  • The ATM VCEP instructions specify that an unaffected individual assessed for a possible downgrade should be at least 18 years old with no evidence of A-T; the case bundle contains no such individual or observation.
  • ClinVar provides a single-submitter Pathogenic classification for the target variant but no unaffected co-occurrence or phase data, so it was not used as BP2 evidence.
  • The extracted findings for PMID:23807571 and PMID:25614872 do not mention c.7628dup or p.(Asn2543LysfsTer5) and contain no unaffected co-occurrence or cis/trans observation relevant to BP2.
Still missing
  • An unaffected adult individual carrying c.7628dup with a VCEP-classified pathogenic/likely pathogenic ATM variant is not documented.
  • Phase evidence establishing trans, cis, or homozygous status is not documented.
  • The age and absence of A-T features required for evaluating an unaffected individual are not documented.
Sources
vcep_atm_pm3_bp2_1_5clinvar ↗PMID:23807571 ↗PMID:25614872 ↗
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: PS1 applies only to missense or splice-region variants; this is a frameshift. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 PS1 specification applies the standard PS1 pathway to missense changes with the same amino-acid change, and its alternative pathway to splice-region variants with comparable splice predictions or observations. This variant is a frameshift, NM_000051.4:c.7628dup, predicted to cause NP_000042.3:p.(Asn2543LysfsTer5), with no qualifying missense or splice-region PS1 pathway applicable.

Rule
ATM_VCEP_v1.5_PS1
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 identifies PS1 as applicable to missense changes with the same amino-acid change, or to splice-region variants meeting the dedicated splice-comparison requirements.
  • Case normalization identifies NM_000051.4:c.7628dup as a frameshift producing NP_000042.3:p.(Asn2543LysfsTer5); it is not a missense or splice-region variant for PS1 purposes.
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 VCEPNot applicable: the ATM VCEP excludes de novo PS2 for autosomal dominant/recessive disease, and no parental testing was available. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 specification states that PS2 is not applicable for autosomal dominant or autosomal recessive disease because informative de novo occurrences have not been observed and de novo autosomal-recessive conditions are unlikely to be informed by phase. The case bundle provides no proband-level parental testing or confirmed maternity/paternity evidence that would override this VCEP restriction.

VCEP rule
ATM VCEP v1.5: PS2 not applicable for autosomal dominant or autosomal recessive disease.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 lists PS2 as not applicable and instructs: do not use for AD or AR disease because informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
  • The consolidated case-evidence bundle contains no documented de novo observation, parental genotypes, or confirmed maternity/paternity for NM_000051.4:c.7628dup.
Still missing
  • No case-specific parental testing or confirmed maternity and paternity data are provided; this does not change the VCEP-defined non-applicability of PS2.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP marks PM1 as not applicable, and this is a frameshift, not a missense variant. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 specification explicitly marks PM1 as Not Applicable. The variant is also a frameshift rather than a missense variant for which a critical functional domain or hotspot assessment would ordinarily be relevant. The bundle's vcep_materials.json contains no domain_tables entry for ATM.

VCEP rule
ATM_VCEP_v1.5_PM1
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 cspec ruleset lists PM1 with applicability: 'Not Applicable'.
  • vcep_materials.json has domain_tables={} for ATM; no authoritative domain-table entry is available, and the VCEP-specific Not Applicable designation governs this criterion.
Sources
cspec ↗
PM4 N/ANot applicable: PM4 is restricted to stop-loss variants; this frameshift creates a premature stop codon. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.5 specification restricts PM4 to stop-loss variants. c.7628dup is a frameshift creating a premature termination codon, not a stop-loss variant; its loss-of-function consequence is evaluated under PVS1 rather than PM4.

Rule
ATM VCEP v1.5 PM4: use for stop-loss variants only.
Evidence considered
  • Case normalization identifies a frameshift consequence, p.(Asn2543LysfsTer5), rather than extension of the native translation terminus.
  • ATM VCEP v1.5 PM4 instruction: use for stop-loss variants.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP excludes assumed de novo status without confirmed parentage, and none was documented. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 specification states that PM6 is not applicable for autosomal dominant or autosomal recessive disease because assumed de novo status without confirmed paternity and maternity is not informative in these disease contexts. No case-specific de novo or parental evidence is documented in the bundle.

VCEP rule
ATM VCEP v1.5: PM6 not applicable for autosomal dominant or autosomal recessive disease.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 lists PM6 as not applicable and instructs: do not use for AD or AR disease because informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
  • The consolidated case-evidence bundle contains no documented assumed-de-novo occurrence, parental genotypes, or confirmed maternity/paternity for NM_000051.4:c.7628dup.
Still missing
  • No case-specific parental testing or confirmed maternity and paternity data are provided; this does not change the VCEP-defined non-applicability of PM6.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP designates PP2 as not applicable. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 specification explicitly marks PP2 as Not Applicable.

VCEP rule
ATM_VCEP_v1.5_PP2
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 cspec ruleset lists PP2 with applicability: 'Not Applicable'.
Sources
cspec ↗
PP3 N/ANot applicable: PP3 covers missense or splice-primary variants; this exonic frameshift is outside those sub-paths (SpliceAI max delta 0.028). Details ▾Hide ▴
Reasoning

ATM VCEP PP3 is specified for missense variants with REVEL >0.7333 and for silent, missense/in-frame, or non-canonical intronic variants with SpliceAI >=0.2. NM_000051.4:c.7628dup is an exonic frameshift (p.Asn2543LysfsTer5), outside these PP3 sub-paths; its SpliceAI maximum delta score of 0.028 also does not meet the splice-impact threshold.

Rule
ATM HBOP VCEP v1.5 PP3: missense REVEL >0.7333; splicing SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor/acceptor ±1,2.
Evidence considered
  • The governing ATM HBOP VCEP v1.5 PP3 rule is REVEL >0.7333 for missense variants or SpliceAI >=0.2 for silent, missense/in-frame, and non-canonical intronic variants.
  • Variant normalization identifies c.7628dup as p.(Asn2543LysfsTer5), an exonic frameshift; SpliceAI maximum delta is 0.028 (DS_AG 0.028, DS_AL 0.002, DS_DG 0.011, DS_DL 0.0).
Sources
cspec ↗spliceai ↗
PP4 VCEPNot applicable: the ATM VCEP designates PP4 as not applicable. Details ▾Hide ▴
Reasoning

PP4 is designated Not Applicable by the governing ATM HBOP VCEP v1.5 specification.

VCEP rule
ATM HBOP VCEP v1.5: PP4 Not Applicable.
Evidence considered
  • The ATM HBOP VCEP v1.5 specification explicitly lists PP4 as Not Applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP designates PP5 as not applicable, and ClinVar has no expert-panel submission. Details ▾Hide ▴
Reasoning

PP5 is designated Not Applicable by the governing ATM HBOP VCEP v1.5 specification. In addition, the exact ClinVar record has only a single clinical-laboratory submission and no expert-panel submission, so it does not meet the required expert-panel condition.

VCEP rule
ATM HBOP VCEP v1.5: PP5 Not Applicable; expert-panel-only policy not satisfied.
Evidence considered
  • The ATM HBOP VCEP v1.5 specification explicitly lists PP5 as Not Applicable.
  • ClinVar variation 4806906 is an exact match but has one Pathogenic Labcorp clinical-testing submission with review status 'criteria provided, single submitter'; the submission audit reports zero expert-panel submissions.
Sources
cspec ↗clinvar ↗
BS2 VCEPNot applicable: the ATM VCEP designates BS2 as not applicable. Details ▾Hide ▴
Reasoning

BS2 is not applicable under the ATM VCEP version 1.5 specification. The framework explicitly designates BS2 as not applicable, so healthy-carrier, homozygote, penetrance, and age-of-onset observations are not used for this criterion.

VCEP rule
ATM VCEP version 1.5: BS2 is not applicable.
Evidence considered
  • The ClinGen HBOP ATM VCEP version 1.5 lists BS2 as not applicable.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP designates BS4 as not applicable. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 specification lists BS4 as not applicable. For the autosomal-recessive ataxia-telangiectasia context, it states that informative instances of lack of co-segregation are too rare to receive weight at this time, and that biallelic unaffected patients may instead be considered for BP2. No non-segregation observation is documented in the case bundle.

VCEP rule
ATM VCEP v1.5: BS4 not applicable; informative lack of co-segregation in A-T families is too rare to receive weight.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 lists BS4 as not applicable and states that informative lack-of-co-segregation instances in A-T families are too rare to be considered for weight at this time.
  • The consolidated case-evidence bundle contains no documented unaffected carrier, biallelic unaffected patient, or other informative non-segregation observation for NM_000051.4:c.7628dup.
Still missing
  • No unaffected carriers, biallelic unaffected individuals, or other informative non-segregation observations are reported; this does not change the VCEP-defined non-applicability of BS4.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP designates BP1 as not applicable. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 specification explicitly marks BP1 as Not Applicable.

VCEP rule
ATM_VCEP_v1.5_BP1
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 cspec ruleset lists BP1 with applicability: 'Not Applicable'.
Sources
cspec ↗
BP3 VCEPNot applicable: BP3 is excluded by the ATM VCEP, and this frameshift duplication is not in-frame. Details ▾Hide ▴
Reasoning

BP3 is explicitly not applicable under the ATM VCEP v1.5 specification. Independently, this variant is a frameshift duplication rather than an in-frame insertion/deletion in a repetitive region, so it does not fit the generic BP3 evidence type.

VCEP rule
ATM VCEP v1.5 BP3: not applicable; do not use.
Evidence considered
  • ATM VCEP v1.5 lists BP3 as not applicable and instructs users not to use it.
  • Case normalization identifies c.7628dup as a frameshift, p.(Asn2543LysfsTer5), not an in-frame alteration.
Sources
cspec ↗
BP4 N/ANot applicable: BP4 sub-paths cover missense or splice-primary variants; this exonic frameshift is neither. Details ▾Hide ▴
Reasoning

The ATM VCEP BP4 computational sub-paths are REVEL <=0.249 for missense variants or SpliceAI <=0.1 where splicing is the primary plausible mechanism. This exonic frameshift is neither a missense variant nor a synonymous/deep-intronic splice-primary variant. The local ATM BP4 policy therefore excludes BP4 from the low SpliceAI score; this is consistent with the policy's direction not to treat a clean splice prediction as benign evidence when the variant's primary protein-level mechanism remains unresolved by that sub-path.

Rule
ATM HBOP VCEP v1.5 BP4, applying the local ATM BP4 mechanism-selection policy: REVEL <=0.249 for missense; SpliceAI <=0.1 only for splice-primary synonymous or non-canonical intronic variants.
Evidence considered
  • The governing ATM HBOP VCEP v1.5 BP4 thresholds are REVEL <=0.249 for missense and SpliceAI <=0.1 for no predicted splice impact.
  • The local ATM BP4 policy limits the splice sub-path to non-missense variants for which splicing is the primary plausible mechanism, specifically synonymous and non-canonical intronic variants; it instructs that a clean SpliceAI score does not establish benign protein-level evidence.
  • c.7628dup is an exonic frameshift, and its SpliceAI maximum delta is 0.028.
Sources
cspec ↗spliceai ↗
BP5 VCEPNot applicable: the ATM VCEP designates BP5 as not applicable. Details ▾Hide ▴
Reasoning

BP5 is designated Not Applicable by the governing ATM HBOP VCEP v1.5 specification.

VCEP rule
ATM HBOP VCEP v1.5: BP5 Not Applicable.
Evidence considered
  • The ATM HBOP VCEP v1.5 specification explicitly lists BP5 as Not Applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP designates BP6 as not applicable, and ClinVar has no expert-panel benign assertion. Details ▾Hide ▴
Reasoning

BP6 is designated Not Applicable by the governing ATM HBOP VCEP v1.5 specification. The exact ClinVar record has no expert-panel benign or likely benign assertion.

VCEP rule
ATM HBOP VCEP v1.5: BP6 Not Applicable; expert-panel-only policy not satisfied.
Evidence considered
  • The ATM HBOP VCEP v1.5 specification explicitly lists BP6 as Not Applicable.
  • ClinVar variation 4806906 is an exact match but has one Pathogenic clinical-laboratory submission and zero expert-panel submissions; it contains no expert-panel Benign or Likely benign assertion.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: BP7 applies to synonymous or deep intronic variants; this is an exonic frameshift. Details ▾Hide ▴
Reasoning

ATM VCEP BP7 applies to synonymous variants and deep intronic variants (>+7 at donor sites or <-21 at acceptor sites), with RNA-based BP7 available only when lack of an aberrant RNA defect is observed. c.7628dup is an exonic frameshift, so BP7 is not applicable.

Rule
ATM HBOP VCEP v1.5 BP7: synonymous or deep intronic (>+7 donor, <-21 acceptor); BP7(RNA) requires observed lack of an aberrant RNA defect.
Evidence considered
  • The governing ATM HBOP VCEP v1.5 BP7 rule is limited to synonymous and defined deep-intronic variants; RNA BP7 requires observed lack of an aberrant RNA defect.
  • Variant normalization identifies c.7628dup as an exonic frameshift encoding p.(Asn2543LysfsTer5).
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.7628dup
Protein (HGVS p.)
NP_000042.3:p.(Asn2543LysfsTer5)
GRCh38
chr11:108331554 T>TA
GRCh37
chr11:108202281 T>TA
Location and type
Exon 51 · frameshift
ClinVar
4806906

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 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 +311 bp
0.002
SpliceAI acceptor gainat -108 bp
0.028
SpliceAI donor lossat -238 bp
0.000
SpliceAI donor gainat +483 bp
0.011
Pangolin splice lossmagnitude shown
-0.008
Pangolin splice gain
0.005

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: PP3 covers missense or splice-primary variants; this exonic frameshift is outside those sub-paths (SpliceAI max delta 0.028). Details ▾Hide ▴
Reasoning

ATM VCEP PP3 is specified for missense variants with REVEL >0.7333 and for silent, missense/in-frame, or non-canonical intronic variants with SpliceAI >=0.2. NM_000051.4:c.7628dup is an exonic frameshift (p.Asn2543LysfsTer5), outside these PP3 sub-paths; its SpliceAI maximum delta score of 0.028 also does not meet the splice-impact threshold.

Rule
ATM HBOP VCEP v1.5 PP3: missense REVEL >0.7333; splicing SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor/acceptor ±1,2.
Evidence considered
  • The governing ATM HBOP VCEP v1.5 PP3 rule is REVEL >0.7333 for missense variants or SpliceAI >=0.2 for silent, missense/in-frame, and non-canonical intronic variants.
  • Variant normalization identifies c.7628dup as p.(Asn2543LysfsTer5), an exonic frameshift; SpliceAI maximum delta is 0.028 (DS_AG 0.028, DS_AL 0.002, DS_DG 0.011, DS_DL 0.0).
Sources
cspec ↗spliceai ↗
BP4 N/ANot applicable: BP4 sub-paths cover missense or splice-primary variants; this exonic frameshift is neither. Details ▾Hide ▴
Reasoning

The ATM VCEP BP4 computational sub-paths are REVEL <=0.249 for missense variants or SpliceAI <=0.1 where splicing is the primary plausible mechanism. This exonic frameshift is neither a missense variant nor a synonymous/deep-intronic splice-primary variant. The local ATM BP4 policy therefore excludes BP4 from the low SpliceAI score; this is consistent with the policy's direction not to treat a clean splice prediction as benign evidence when the variant's primary protein-level mechanism remains unresolved by that sub-path.

Rule
ATM HBOP VCEP v1.5 BP4, applying the local ATM BP4 mechanism-selection policy: REVEL <=0.249 for missense; SpliceAI <=0.1 only for splice-primary synonymous or non-canonical intronic variants.
Evidence considered
  • The governing ATM HBOP VCEP v1.5 BP4 thresholds are REVEL <=0.249 for missense and SpliceAI <=0.1 for no predicted splice impact.
  • The local ATM BP4 policy limits the splice sub-path to non-missense variants for which splicing is the primary plausible mechanism, specifically synonymous and non-canonical intronic variants; it instructs that a clean SpliceAI score does not establish benign protein-level evidence.
  • c.7628dup is an exonic frameshift, and its SpliceAI maximum delta is 0.028.
Sources
cspec ↗spliceai ↗
BP7 N/ANot applicable: BP7 applies to synonymous or deep intronic variants; this is an exonic frameshift. Details ▾Hide ▴
Reasoning

ATM VCEP BP7 applies to synonymous variants and deep intronic variants (>+7 at donor sites or <-21 at acceptor sites), with RNA-based BP7 available only when lack of an aberrant RNA defect is observed. c.7628dup is an exonic frameshift, so BP7 is not applicable.

Rule
ATM HBOP VCEP v1.5 BP7: synonymous or deep intronic (>+7 donor, <-21 acceptor); BP7(RNA) requires observed lack of an aberrant RNA defect.
Evidence considered
  • The governing ATM HBOP VCEP v1.5 BP7 rule is limited to synonymous and defined deep-intronic variants; RNA BP7 requires observed lack of an aberrant RNA defect.
  • Variant normalization identifies c.7628dup as an exonic frameshift encoding p.(Asn2543LysfsTer5).
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

9 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.
    The paper does not mention ATM c.7628dup or NP_000042.3:p.(N2543Kfs*5). It describes ATM biology and states that the functional impact of each individual mutation is not established; it does not provide a variant-specific assay result.
    Does not name this variant
    PMID 27413114 ↗
    Quoted passage
    Not every identified somatic mutation correlates with one known to cause A-T syndrome, and the functional impact of each somatic mutation is not established. Therefore, it is difficult to predict whether a certain mutation is deleterious or a variant without functional significance.

    Somatic ATM Mutations in Cancer

  • Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
    The paper does not explicitly mention ATM c.7628dup or NP_000042.3:p.(N2543Kfs*5). It investigates ATM loss and catalytically inactive Atm in mouse CNS models and therefore does not provide a direct functional result for this variant.
    Does not name this variant
    PMID 30348496 ↗
    Quoted passage
    Importantly, the delay in DSB repair was greater in PCs in Atm-KD-CNS cultures than in those of Atm-Δ-CNS mice compared to the Atmfl/fl genotype (Fig. 3c, d). This result suggests that the presence of kinase-dead Atm in the CNS exerts a more pronounced effect on DSB repair than Atm absence.

    Results, section 3.3

  • Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
    No paper-specific finding is recorded.
    PMID 30553448 ↗
  • Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.
    Huang Y et al. · 2013
    The paper does not explicitly mention ATM c.7628dup or NP_000042.3:p.(N2543Kfs*5). It reports sequencing and MLPA findings in Chinese ataxia-telangiectasia patients but no variant-specific functional assay result for this variant.
    Does not name this variant
    PMID 23807571 ↗
    Quoted passage
    The majority of Atm mutations are frameshift or nonsense mutations (Wright et al. 1996; Concannon and Gatti 1997), which are predicted to truncate the whole ATM protein.

    Introduction; Results, mutation analysis; Materials and Methods, Mutation Screening

  • Ten new ATM alterations in Polish patients with ataxia-telangiectasia.
    Podralska MJ et al. · 2014
    The paper does not explicitly mention ATM c.7628dup or NP_000042.3:p.(N2543Kfs*5). It reports analysis of ATM in 26 patients from 24 unrelated Polish families, identifying 38 sequence alterations, including nonsense and frameshift variants that truncate the ATM protein. The study used sequencing of all ATM exons and exon/intron boundaries, together with SSCP/heteroduplex analysis and MLPA; no variant-specific functional or segregation findings are reported for c.7628dup.
    Does not name this variant
    PMID 25614872 ↗
    Quoted passage
    The mutation types are diverse, including 21 nonsense (55.3%), 12 splicing (31.6%), 3 large genomic deletions (7.9%) and 2 missense alterations (5.3%).

    Results and Discussion, first paragraph; Materials and Methods, Patients and Molecular analysis

  • Hereditary Ataxia Overview.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301317 ↗
  • Ataxia-Telangiectasia.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301790 ↗
  • EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
    van de Warrenburg BP et al. · 2014
    This clinical consensus paper does not mention ATM c.7628dup or NP_000042.3:p.(N2543Kfs*5). Its general statement about ataxia-telangiectasia does not provide exact-variant case-control enrichment evidence for PS4.
    Does not name this variant
    PMID 24418350 ↗
    Quoted passage
    The second most frequent recessive ataxia globally is ataxia telangiectasia, with the exception of North Africa where this is ataxia with vitamin E deficiency [15,16].

    Recessive family history

  • EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
    Gasser T et al. · 2010
    No paper-specific finding is recorded.
    PMID 20050888 ↗

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 0.028 Open source ↗
ClinVar 1 Pathogenic 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 has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 4806906)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

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.