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ATMc.8292_8293delPathogenic
Print report
Variant interpretation report

ATM c.8292_8293del, p.(Ser2764ArgfsTer4)

NM_000051.4:c.8292_8293del NP_000042.3:p.(Ser2764ArgfsTer4) Frameshift · exon 57 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, very strong: the frameshift terminates at approximately p.2767, upstream of ATM's p.Arg3047 pathogenic truncation boundary.

PM2Supporting
PM2 · supporting

Met at supporting: gnomAD v4.1 total AF is 1.858874e-6 (0.0001859%), below the ATM VCEP PM2 threshold of <=0.001%.

PM5Supporting
PM5 · supporting

Met, supporting: p.(Ser2764ArgfsTer4) is a frameshift termination upstream of the ATM VCEP PM5 cutoff at p.Arg3047.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: PVS1 (very strong) plus PM2 and PM5 (supporting) satisfy ATM VCEP v1.5 Rule4.

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
3 / 1,613,880 alleles

gnomAD v4.1: 3 / 1,613,880 alleles. Recorded AF 1.85887e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.07304e-06; MAF= 0.00071%, 2/282764 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.54904e-05; MAF= 0.00155%, 2/129112 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.170 maximum delta

Recorded SpliceAI maximum delta score: 0.170. Refer to the recorded PP3/BP4 rationale for interpretation.

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

7 Pathogenic · 1 Likely pathogenic.

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

For ATM, the governing HBOP VCEP v1.5 specification takes precedence: PP4, PP5, BP5, and BP6 are not applicable, while PS4 requires a qualifying case-control result.

No exact-variant case-control enrichment statistic meeting the ATM PS4 rule was identified, and ordinary ClinVar submissions do not activate PP5 or BP6.

Met · 3

PVS1 Very strongMet, very strong: the frameshift terminates at approximately p.2767, upstream of ATM's p.Arg3047 pathogenic truncation boundary. Details ▾Hide ▴
Reasoning

NM_000051.4:c.8292_8293del is a two-nucleotide coding frameshift producing NP_000042.3:p.(Ser2764ArgfsTer4), a premature termination at approximately residue 2767. The ATM HBOP VCEP v1.5 PVS1 specification recognizes frameshift variants as null variants in ATM, establishes the default transcript NM_000051.3/ENST00000278616.8 as relevant, and states that all exons in that transcript are constitutive without major rescue isoforms. The predicted termination is upstream of the VCEP's most 3-prime pathogenic truncation boundary at p.Arg3047, so this is not an extreme C-terminal truncation under the stated ATM rule. No named VCEP or SVI downgrade rule is supported by the available evidence: this is not a splice event, no exon-skipping rescue is implicated, and no evidence shows escape from NMD or a biologically irrelevant exon. Apply full-strength PVS1 as very strong. The searched ATM_PVS1_1.5.pdf file contains no variant-specific entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4; the call therefore follows the governing ATM PVS1 rule rather than a pre-assigned row.

Rule
ATM HBOP VCEP v1.5 PVS1 decision tree for null frameshift variants; full-strength PVS1 is very strong.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8292_8293del as a frameshift encoding NP_000042.3:p.(Ser2764ArgfsTer4) / p.(S2764Rfs*4).
  • ATM HBOP VCEP v1.5 PVS1 defines frameshift variants as null variants when loss of function is a known disease mechanism, specifies NM_000051.3/ENST00000278616.8 as the default transcript, and considers all exons in that transcript constitutive without major rescue isoforms.
  • ATM HBOP VCEP v1.5 identifies p.Arg3047 as the most 3-prime/C-terminal residue considered pathogenic; the predicted stop near p.2767 is upstream of that boundary.
  • The ATM framework records germline loss of function as an established disease mechanism and supplies a default very-strong PVS1 assessment for this frameshift; no evidence supports an NMD-escape, non-critical-exon, or splice-specific downgrade.
Still missing
  • No variant-specific entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in ATM_PVS1_1.5.pdf.
  • The available record does not directly document RNA-level NMD or the precise coding-exon number; no downgrade is applied because no named downgrade rule is evidenced.
Sources
cspec ↗vcep_atm_pvs1_1_5pvs1_variant_assessment
PM2 SupportingMet at supporting: gnomAD v4.1 total AF is 1.858874e-6 (0.0001859%), below the ATM VCEP PM2 threshold of <=0.001%. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 limits PM2 to Supporting and specifies frequency <=0.001% in gnomAD v4.1; it also states that one allele in a single subpopulation is sufficient. The variant is present at total AF 1.858874e-6 (0.0001859%; 3/1,613,880 alleles), with gnomAD v4.1 grpmax FAF 6.8e-7 (0.000068%), highest subpopulation AF 2.542515e-6 (0.0002543%), and no homozygotes. These values meet the VCEP PM2 Supporting threshold. The specification does not require a non-cancer or exome-only subset, so the combined all-comers gnomAD v4.1 data are the applicable source.

Rule
PM2 Supporting: frequency <=0.001% in gnomAD v4.1 dataset
Evidence considered
  • ATM VCEP v1.5 PM2 rule: use PM2 Supporting for frequency <=0.001% in gnomAD v4.1; one allele in a single subpopulation is sufficient.
  • gnomAD v4.1 reports total AF 1.858874e-6 (0.0001859%; 3/1,613,880 alleles), grpmax FAF 6.8e-7, highest observed subpopulation AF 2.542515e-6 in European (non-Finnish) individuals, and homozygotes = 0.
  • The ATM VCEP specifies gnomAD v4.1 without a non-cancer or exome-only restriction for PM2, so the combined all-comers gnomAD v4.1 values are used.
Sources
cspec ↗gnomad_v4 ↗
PM5 SupportingMet, supporting: p.(Ser2764ArgfsTer4) is a frameshift termination upstream of the ATM VCEP PM5 cutoff at p.Arg3047. Details ▾Hide ▴
Reasoning

Met at Supporting strength: the ATM VCEP v1.5 PM5 rule specifically applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047. NM_000051.4:c.8292_8293del produces p.(Ser2764ArgfsTer4), a premature termination approximately 283 residues upstream of p.Arg3047, satisfying the gene-specific cutoff rule. No same-residue missense comparator is required under this ATM-specific PM5 rule.

Rule
ATM VCEP v1.5 PM5 Supporting: apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 PM5 rule states: apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, with Supporting strength specified.
  • The variant is NM_000051.4:c.8292_8293del, producing NP_000042.3:p.(Ser2764ArgfsTer4), a premature termination far upstream of p.Arg3047.
Sources
cspec ↗

Not met · 2 · evaluated, threshold not reached

BA1 Not met: gnomAD v4.1 grpmax FAF is 6.8e-7 (0.000068%), below the ATM VCEP BA1 threshold of >0.5%. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 specifies BA1 as grpmax filtering AF >0.5% in gnomAD v4.1. The all-comers gnomAD v4.1 record has grpmax FAF 6.8e-7 (0.000068%), total AF 1.858874e-6 (0.0001859%), and highest subpopulation AF 2.542515e-6 (0.0002543%), all well below 0.5%. The specification does not require a non-cancer or exome-only subset for this criterion, so the combined all-comers gnomAD v4.1 data are the applicable source.

Rule
Grpmax Filtering AF >0.5% in gnomAD v4.1 dataset
Evidence considered
  • ATM VCEP v1.5 BA1 rule: apply stand-alone benign evidence when grpmax filtering AF is >0.5% in gnomAD v4.1.
  • gnomAD v4.1 reports grpmax FAF 6.8e-7, total AF 1.858874e-6 from 3/1,613,880 alleles, and highest observed subpopulation AF 2.542515e-6 in European (non-Finnish) individuals; homozygotes = 0.
  • The ATM VCEP specifies gnomAD v4.1 without a non-cancer or exome-only restriction for BA1, so the combined all-comers gnomAD v4.1 values are used.
Sources
cspec ↗gnomad_v4 ↗
BS1 Not met: gnomAD v4.1 grpmax FAF is 6.8e-7 (0.000068%), below the ATM VCEP BS1 threshold of >0.05%. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 specifies BS1 as grpmax filtering AF >0.05% in gnomAD v4.1. The all-comers gnomAD v4.1 record has grpmax FAF 6.8e-7 (0.000068%), total AF 1.858874e-6 (0.0001859%), and highest subpopulation AF 2.542515e-6 (0.0002543%), each below 0.05%. The specification does not require a non-cancer or exome-only subset for this criterion, so the combined all-comers gnomAD v4.1 data are the applicable source.

Rule
Grpmax Filtering AF >0.05% in gnomAD v4.1 dataset
Evidence considered
  • ATM VCEP v1.5 BS1 rule: apply strong benign evidence when grpmax filtering AF is >0.05% in gnomAD v4.1.
  • gnomAD v4.1 reports grpmax FAF 6.8e-7, total AF 1.858874e-6 from 3/1,613,880 alleles, and highest observed subpopulation AF 2.542515e-6 in European (non-Finnish) individuals; homozygotes = 0.
  • The ATM VCEP specifies gnomAD v4.1 without a non-cancer or exome-only restriction for BS1, so the combined all-comers gnomAD v4.1 values are used.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 6 · no assessment recorded

PS3 Not assessed: no qualifying ATM-specific assay result was documented for c.8292_8293del, so the VCEP PS3 strength thresholds cannot be applied. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.5 specification permits PS3_Supporting when a tested variant fails to rescue an ATM-specific feature such as phosphorylation of ATM-specific targets, and PS3_Moderate only when qualifying radiosensitivity evidence is combined with kinase-activity evidence; strong PS3 is not permitted. The approved-assay table identifies Mitui 2009 (PMID:18634022), Barone 2009 (PMID:19431188), and Scott 2002 (PMID:11805335) as qualifying kinase assays, with radiosensitivity usable only under the stated combination rule. The queried variant, NM_000051.4:c.8292_8293del (p.Ser2764ArgfsTer4; p.S2764Rfs*4), was not found under any of the three requested notations in the governing ATM full-text files, including the approved-assay methodology table and Sun et al. Table S1 (PMID:40580951). The available case paper extracts likewise do not document this exact variant in a qualifying assay. Therefore no variant-specific validated functional result can be assigned PS3 from the supplied evidence.

Rule
ATM VCEP v1.5: do not use PS3 as Strong; PS3_Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity; PS3_Supporting requires failure to rescue an ATM-specific feature only; do not use radiosensitivity alone.
Evidence considered
  • ATM VCEP v1.5 states that PS3 must not be used as Strong; PS3_Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity, while PS3_Supporting applies to failure of an ATM-specific feature alone and radiosensitivity-only evidence receives no weight.
  • The governing ATM assay table lists approved kinase-activity assays in PMID:18634022, PMID:19431188, and PMID:11805335, but it does not report results for the current variant; its calibrated kinase readouts are based on ATM-substrate phosphorylation relative to wild-type and null controls.
  • The full-text searches found no occurrence of c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 in the governing ATM VCEP files, including the approved-assay table and Suppl_TableS1_PMID 40580951.xlsx.txt.
Still missing
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt; this file is a methodology and calibration table, not a per-variant results table.
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in Suppl_TableS1_PMID 40580951.xlsx.txt; Table S1 is an ATM SNV table and contains no row for this frameshift variant.
  • The variant was not documented in the available extracts for the qualifying ATM functional-assay papers PMID:18634022, PMID:19431188, or PMID:11805335; direct variant-level assay results from those papers remain unavailable.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951PMID:23807571 ↗PMID:25614872 ↗PMID:31050087 ↗
PS4 Not assessed: no qualifying case-control p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval was available for this exact variant. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.5 specification makes PS4 applicable at strong strength only when a case-control study reports p-value ≤.05 and either odds ratio, hazard ratio, or relative risk ≥2 or lower 95% confidence interval ≥1.5. The available evidence contains no case-control analysis or exact-variant quantitative enrichment result meeting those required fields. The literature extracts for PMID:23807571, PMID:25614872, and PMID:31050087 describe disease cohorts or ATM variant cohorts but do not mention NM_000051.4:c.8292_8293del specifically and do not provide a qualifying case-control statistic for it. Therefore PS4 cannot be assessed from the available evidence.

Rule
Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).
Evidence considered
  • ATM HBOP VCEP v1.5 states: Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5).
  • PMID:23807571, PMID:25614872, and PMID:31050087 report ATM/ataxia-telangiectasia cohorts or variant cohorts, but their extracted findings do not mention the exact queried variant or provide its qualifying case-control enrichment statistic.
Still missing
  • An exact-variant case-control study with p-value and odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is unavailable.
Sources
cspec ↗PMID:23807571 ↗PMID:25614872 ↗PMID:31050087 ↗
PM3 Not assessed: no affected-proband observation documents this variant with a second ATM pathogenic variant in trans or qualifying homozygosity for PM3 points. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 PM3/BP2 specification requires affected Ataxia-Telangiectasia proband observations and weighs phase with a pathogenic or likely pathogenic ATM variant: confirmed trans receives 4.0 points for a confident phenotype or 2.0 for a consistent phenotype, phase unknown receives 2.0 or 1.0, and homozygosity receives 2.0 or 1.0, with PM3 Supporting at 1.0 point, Moderate at 2.0, Strong at 4.0, and Very Strong at 8.0. The variant is sufficiently rare for consideration (gnomAD v4.1 grpmax FAF 6.8e-07), but the available case evidence does not document an affected proband carrying NM_000051.4:c.8292_8293del with a second ATM pathogenic/likely pathogenic variant, confirmed phase, or qualifying homozygosity. The governing file ATM_PM3_BP2_1.5.pdf was searched under c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4, with no variant-specific table entry found; the available literature extracts likewise report no exact-variant observation. Therefore no PM3 points can be assigned from the supplied evidence.

Rule
ClinGen HBOP ATM VCEP v1.5 PM3/BP2 points table: PM3 Supporting = 1.0 point, Moderate = 2.0 points, Strong = 4.0 points, Very Strong = 8.0 points; assign points by affected-proband phenotype and phase.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 assigns 4.0 PM3 points for a confident-phenotype affected proband with confirmed trans phase, 2.0 points for phase unknown, 2.0 points for a consistent-phenotype confirmed-trans observation, and converts 1.0, 2.0, 4.0, and 8.0 points to Supporting, Moderate, Strong, and Very Strong PM3, respectively.
  • gnomAD v4.1 reports this variant at grpmax FAF 6.8e-07, below the VCEP's 0.01% general-frequency ceiling for PM3 consideration.
  • Searches of ATM_PM3_BP2_1.5.pdf for c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4 found no variant-specific table entry.
  • The extracted findings for PMID:23807571, PMID:25614872, and PMID:31050087 state that the exact variant was not mentioned and provide no variant-specific phase or affected-proband data.
Still missing
  • No affected Ataxia-Telangiectasia proband record with this variant and a second ATM pathogenic/likely pathogenic variant, including phase, is available.
  • No qualifying homozygous affected individual or phenotype classification is documented.
  • No variant-specific entry was found in ATM_PM3_BP2_1.5.pdf after searching c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5gnomad_v4 ↗PMID:23807571 ↗PMID:25614872 ↗PMID:31050087 ↗
PP1 Not assessed: zero affected-relative segregations are documented, versus the ATM VCEP threshold of one affected relative for PP1 supporting. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PP1 for autosomal-recessive disease based on segregation in affected relatives: supporting for 1, moderate for 2, and strong for at least 3 affected relatives. The available evidence for this variant contains no documented affected relatives, family pedigree, parental testing, phase information, or meiosis count, and the reviewed ATM patient-cohort papers do not mention this exact variant or provide variant-specific segregation data. Therefore, PP1 cannot be assigned.

Rule
AR Condition: segregation in 1 affected relative = Supporting; segregation in 2 affected relatives = Moderate; segregation in ≥3 affected relatives = Strong.
Evidence considered
  • The ATM VCEP PP1 rule assigns supporting strength for segregation in 1 affected relative, moderate for 2, and strong for at least 3 affected relatives.
  • The Chinese ATM patient study covered eight patients from six unrelated families but its extracted finding does not mention c.8292_8293del or report variant-specific segregation for it.
  • The Polish ATM patient study covered 24 unrelated ataxia-telangiectasia families but its extracted finding does not mention c.8292_8293del or report variant-specific segregation for it.
Still missing
  • Variant-specific family segregation data, including affected relatives and their genotypes, are not documented.
Sources
cspec ↗PMID:23807571 ↗PMID:25614872 ↗
BS3 Not assessed: no variant-specific rescue of ATM function or radiosensitivity was documented, so the VCEP BS3 thresholds cannot be applied. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.5 specification permits BS3_Supporting when a variant rescues either an ATM-specific feature or radiosensitivity, and BS3_Moderate when it rescues both; the governing assay table further requires that radiosensitivity be interpreted with kinase-activity evidence and not alone. The queried variant, NM_000051.4:c.8292_8293del (p.Ser2764ArgfsTer4; p.S2764Rfs*4), was not found under any of the three requested notations in the governing ATM full-text files, including the approved-assay methodology table and Sun et al. Table S1 (PMID:40580951). The available case paper extracts do not document a variant-specific rescue result. Consequently, there is no validated benign functional result sufficient to assess BS3.

Rule
ATM VCEP v1.5: BS3_Moderate requires rescue of both an ATM-specific feature and radiosensitivity; BS3_Supporting requires rescue of either; radiosensitivity alone is not weighted.
Evidence considered
  • ATM VCEP v1.5 states that BS3_Moderate requires rescue of both an ATM-specific feature and radiosensitivity, while BS3_Supporting applies when either feature is rescued.
  • The governing ATM assay table defines normal kinase activity relative to wild-type controls and identifies radiosensitivity thresholds, but it does not report a result for the current variant and states that radiosensitivity alone receives no weight.
  • The full-text searches found no occurrence of c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 in the governing ATM VCEP files, including the approved-assay table and Suppl_TableS1_PMID 40580951.xlsx.txt.
Still missing
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt; this file is a methodology and calibration table, not a per-variant results table.
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in Suppl_TableS1_PMID 40580951.xlsx.txt; Table S1 is an ATM SNV table and contains no row for this frameshift variant.
  • The variant was not documented in the available extracts for the qualifying ATM functional-assay papers PMID:18634022, PMID:19431188, or PMID:11805335; direct variant-level normal/rescue assay results remain unavailable.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951PMID:23807571 ↗PMID:25614872 ↗PMID:31050087 ↗
BP2 Not assessed: no unaffected adult carrying this variant with a pathogenic ATM variant in trans or qualifying homozygosity is documented. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 BP2 specification assigns negative points when an unaffected non-A-T adult carries the variant with a pathogenic or likely pathogenic ATM variant in trans: -4.0 for confirmed trans, -2.0 for phase unknown, and for homozygous observations -2.0 in a laboratory setting or -1.0 in a database setting, with BP2 Supporting at -1.0 point, Moderate at -2.0, and Strong at ≤-4.0. The available population data show zero homozygotes in gnomAD v4.1 but do not establish an unaffected adult clinical observation or a pathogenic variant in trans; population allele counts cannot be converted into BP2 points under the VCEP table. The governing file ATM_PM3_BP2_1.5.pdf was searched under c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4, with no variant-specific table entry found. No qualifying unaffected non-A-T adult with phase information is documented, so BP2 cannot be assigned.

Rule
ClinGen HBOP ATM VCEP v1.5 PM3/BP2 points table: BP2 Supporting = -1.0 point, Moderate = -2.0 points, Strong = ≤-4.0 points; use only qualifying unaffected non-A-T adult or phenotyped cohort observations.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 assigns -4.0 BP2 points for confirmed trans, -2.0 for phase unknown, -2.0 for a laboratory-setting homozygous observation, and -1.0 for a database-setting homozygous observation; BP2 strength thresholds are Supporting at -1.0, Moderate at -2.0, and Strong at ≤-4.0.
  • gnomAD v4.1 reports zero homozygotes, but the VCEP restricts homozygous BP2 use to phenotyped individuals from clinical or research cohorts and does not permit frequency-based observations for this purpose.
  • Searches of ATM_PM3_BP2_1.5.pdf for c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4 found no variant-specific table entry.
  • The supplied exact-variant literature extracts contain no qualifying unaffected-adult, co-occurrence, or phase observation.
Still missing
  • No unaffected non-A-T adult over 18 with this variant and a pathogenic/likely pathogenic ATM variant in confirmed trans or phase-unknown configuration is documented.
  • No qualifying clinical or research-cohort homozygous unaffected adult observation is documented; gnomAD zero homozygotes is not sufficient for BP2 points.
  • No variant-specific entry was found in ATM_PM3_BP2_1.5.pdf after searching c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5gnomad_v4 ↗PMID:23807571 ↗PMID:25614872 ↗PMID:31050087 ↗
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP PS1 scope for same-amino-acid missense or qualifying splice-region comparisons. Details ▾Hide ▴
Reasoning

Not applicable: NM_000051.4:c.8292_8293del is a frameshift variant producing p.(Ser2764ArgfsTer4), whereas the ATM VCEP PS1 specification addresses missense variants with the same amino-acid change or splice-region variants meeting its splicing-table prerequisites. The governing ATM_PS1_1.5.pdf was searched for c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4; no entry for this variant was found.

Rule
ATM VCEP v1.5 PS1: same amino-acid change for missense variants with splicing ruled out, or qualifying matched splice events under the ATM PS1 splicing table.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 PS1 specification applies PS1 to missense changes when splicing is ruled out for both alterations, or to splice-region variants meeting the ATM PS1 splicing-table prerequisites.
  • The variant is normalized as NM_000051.4:c.8292_8293del, NP_000042.3:p.(Ser2764ArgfsTer4) / p.(S2764Rfs*4), a frameshift consequence.
  • ATM_PS1_1.5.pdf was searched under c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4, with no matching entry found.
Still missing
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in ATM_PS1_1.5.pdf; the file was searched under all three notations.
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 VCEPNot applicable: the ATM VCEP excludes PS2 for both ATM autosomal-dominant and autosomal-recessive disease contexts. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP version 1.5 specifies that PS2 is not applicable for ATM-related autosomal dominant or autosomal recessive disease because informative de novo occurrences have not been observed and de novo autosomal-recessive disease is not meaningfully informed by phase. No case-specific de novo observation is documented for NM_000051.4:c.8292_8293del.

VCEP rule
Do not use for AD or AR disease: informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 marks PS2 not applicable and instructs not to use it for autosomal-dominant or autosomal-recessive disease.
Sources
cspec ↗
PM1 VCEPNot applicable: ATM VCEP v1.5 marks PM1 not applicable, and frameshift p.(Ser2764ArgfsTer4) is not a missense domain or hotspot observation. Details ▾Hide ▴
Reasoning

Not applicable: the ATM VCEP v1.5 framework marks PM1 as not applicable, and this frameshift variant is not a missense change for which a critical functional domain or hotspot would provide PM1 evidence. The case vcep_materials.json domain_tables object contains no ATM domain-table entry to evaluate.

VCEP rule
ATM VCEP v1.5 PM1: Not Applicable.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 framework explicitly lists PM1 as Not Applicable.
  • The variant is a frameshift, p.(Ser2764ArgfsTer4), rather than a missense variant for which critical-domain or hotspot evidence is assessed under PM1.
  • The case-specific vcep_materials.json domain_tables object is empty.
Still missing
  • vcep_materials.json contains no ATM entry under domain_tables; no authoritative VCEP domain list was available for residue-level review.
Sources
cspec ↗
PM4 N/ANot applicable: PM4 is restricted to stop-loss variants, whereas this variant is a frameshift with a premature termination signal. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.5 specification limits PM4 to stop-loss variants. NM_000051.4:c.8292_8293del is a frameshift with a premature termination signal, not a stop-loss or in-frame protein-length extension, so PM4 is not applicable.

Rule
ATM HBOP VCEP v1.5 PM4: use for stop-loss variants.
Evidence considered
  • The ATM HBOP VCEP v1.5 rule for PM4 states: use for stop-loss variants.
  • The case normalization classifies this alteration as a frameshift producing p.(Ser2764ArgfsTer4), which is incompatible with the VCEP's stop-loss-only PM4 applicability.
Still missing
  • No variant-specific entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in ATM_PVS1_1.5.pdf; the governing PM4 rule is criterion-level rather than a variant table.
Sources
cspec ↗vcep_atm_pvs1_1_5
PM6 VCEPNot applicable: the ATM VCEP excludes PM6 for both ATM autosomal-dominant and autosomal-recessive disease contexts. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP version 1.5 specifies that PM6 is not applicable for ATM-related autosomal dominant or autosomal recessive disease because assumed de novo observations without confirmed maternity and paternity are not informative in these disease contexts. No case-specific assumed de novo observation is documented for NM_000051.4:c.8292_8293del.

VCEP rule
Do not use for AD or AR disease: informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 marks PM6 not applicable and instructs not to use it for autosomal-dominant or autosomal-recessive disease.
Sources
cspec ↗
PP2 VCEPNot applicable: ATM VCEP v1.5 marks PP2 not applicable, and this variant is a frameshift rather than a missense substitution. Details ▾Hide ▴
Reasoning

Not applicable: the ATM VCEP v1.5 framework marks PP2 as not applicable, and PP2 is a missense-oriented gene-level criterion that cannot be applied to this frameshift variant producing p.(Ser2764ArgfsTer4).

VCEP rule
ATM VCEP v1.5 PP2: Not Applicable.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 framework explicitly lists PP2 as Not Applicable.
  • The variant is normalized as p.(Ser2764ArgfsTer4), a frameshift consequence rather than a missense substitution.
Sources
cspec ↗
PP3 N/ANot applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP PP3 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000051.4:c.8292_8293del is a frameshift variant producing p.(Ser2764ArgfsTer4), not a missense or splice-region/intronic variant. The ATM VCEP PP3 specification applies to missense variants through REVEL or to splicing variants through SpliceAI; therefore PP3 must not be evaluated for this protein-length-changing variant. The governing VCEP lookup file Suppl_TableS1_PMID 40580951.xlsx was searched for c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4, with no matching entry found.

Rule
ATM VCEP v1.5 PP3: missense REVEL >0.7333; splicing SpliceAI >=0.2.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 specification defines PP3 for missense variants using REVEL >0.7333 and for splicing variants using SpliceAI >=0.2; it does not make PP3 applicable to frameshift variants.
  • The variant is normalized as NM_000051.4:c.8292_8293del, p.(Ser2764ArgfsTer4), a frameshift consequence.
  • Suppl_TableS1_PMID 40580951.xlsx was searched under c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4; no matching row was found.
Still missing
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in Suppl_TableS1_PMID 40580951.xlsx; this file is a governing lookup for PP3 but does not change the variant's out-of-scope status.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
PP4 VCEPNot applicable: ATM VCEP 1.5 prohibits separate PP4 use for breast cancer and incorporates ataxia-telangiectasia phenotype evidence into PM3/BP2. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.5 specification marks PP4 not applicable. For autosomal dominant breast cancer, it states not to use PP4 because breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic disease; for autosomal recessive ataxia-telangiectasia, phenotype evidence is incorporated into the PM3/BP2 framework rather than used as a separate line of evidence. This variant is therefore not assigned PP4.

VCEP rule
Not applicable under ATM HBOP VCEP v1.5.
Evidence considered
  • ATM HBOP VCEP v1.5 marks PP4 not applicable and directs that phenotype evidence for autosomal recessive ataxia-telangiectasia be handled within PM3/BP2 rather than as separate PP4.
Sources
cspec ↗
PP5 VCEPNot applicable: ATM VCEP 1.5 does not use PP5, and ClinVar lists zero expert-panel submissions for this exact variant. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.5 specification marks PP5 not applicable. In addition, the exact ClinVar record for NM_000051.4:c.8292_8293del has review status criteria provided, single submitter, and zero expert-panel submissions; its Pathogenic and Likely pathogenic assertions are ordinary laboratory or non-expert submissions and cannot trigger PP5 under the stated rule. No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.

VCEP rule
Apply only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; not applicable under ATM HBOP VCEP v1.5.
Evidence considered
  • ATM HBOP VCEP v1.5 marks PP5 not applicable.
  • ClinVar exact-variant record reports criteria provided, single submitter and expert-panel submissions: 0; the available Pathogenic/Likely pathogenic assertions are not expert-panel classifications.
Sources
cspec ↗clinvar ↗
BS2 VCEPNot applicable: the ATM VCEP v1.5 explicitly excludes BS2, regardless of the gnomAD v4.1 homozygote count of 0. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP v1.5 marks BS2 as not applicable. Although gnomAD v4.1 reports no observed homozygotes for this allele, that population observation cannot override the VCEP's explicit exclusion of BS2.

VCEP rule
BS2 is not applicable under ClinGen HBOP ATM VCEP v1.5
Evidence considered
  • ATM VCEP v1.5 lists BS2 as not applicable.
  • gnomAD v4.1 reports homozygotes = 0, but this does not change the governing VCEP applicability decision.
Sources
cspec ↗gnomad_v4 ↗
BS4 VCEPNot applicable: BS4 is excluded by the ATM VCEP version 1.5 specification. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP version 1.5 specifies BS4 as not applicable. No non-segregation observation in an informative affected family is documented for NM_000051.4:c.8292_8293del.

VCEP rule
Not applicable under the ClinGen HBOP ATM VCEP version 1.5 specification.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 marks BS4 not applicable.
Sources
cspec ↗
BP1 VCEPNot applicable: ATM VCEP v1.5 marks BP1 not applicable, and this variant is a frameshift rather than a missense substitution. Details ▾Hide ▴
Reasoning

Not applicable: the ATM VCEP v1.5 framework marks BP1 as not applicable, and BP1 is a missense-oriented benign criterion that cannot be applied to this frameshift variant producing p.(Ser2764ArgfsTer4).

VCEP rule
ATM VCEP v1.5 BP1: Not Applicable.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 framework explicitly lists BP1 as Not Applicable.
  • The variant is normalized as p.(Ser2764ArgfsTer4), a frameshift consequence rather than a missense substitution.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP marks BP3 not applicable, and this variant is a truncating frameshift rather than an in-frame repeat-region indel. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.5 specification marks BP3 as not applicable. In addition, this variant is a coding frameshift predicted to truncate ATM rather than an in-frame deletion or insertion in a repetitive region, so BP3 does not apply.

VCEP rule
ATM HBOP VCEP v1.5 BP3: Not Applicable.
Evidence considered
  • The ATM HBOP VCEP v1.5 criterion specification explicitly lists BP3 as Not Applicable.
  • The case normalization identifies a two-nucleotide coding frameshift with a premature termination at approximately residue 2767, not an in-frame deletion or insertion in a repetitive region.
Still missing
  • No variant-specific entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in ATM_PVS1_1.5.pdf; BP3 is governed by the ATM specification's not-applicable designation.
Sources
cspec ↗vcep_atm_pvs1_1_5
BP4 N/ANot applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP BP4 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000051.4:c.8292_8293del is a frameshift variant producing p.(Ser2764ArgfsTer4), not a missense or splice-region/intronic variant. The ATM VCEP BP4 specification applies to missense variants through REVEL <=0.249 or to splicing variants through SpliceAI <=0.1; the case-specific policy also requires mechanism-appropriate evaluation and does not extend BP4 to truncating variants. Therefore BP4 must not be evaluated for this protein-length-changing variant. The governing VCEP lookup file Suppl_TableS1_PMID 40580951.xlsx was searched for c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4, with no matching entry found.

Rule
ATM VCEP v1.5 BP4: missense REVEL <=0.249; splicing SpliceAI <=0.1.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 specification defines BP4 for missense variants using REVEL <=0.249 or for splicing variants using SpliceAI <=0.1; it does not make BP4 applicable to frameshift variants.
  • The variant is normalized as NM_000051.4:c.8292_8293del, p.(Ser2764ArgfsTer4), a frameshift consequence.
  • Suppl_TableS1_PMID 40580951.xlsx was searched under c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4; no matching row was found.
Still missing
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in Suppl_TableS1_PMID 40580951.xlsx; this file is a governing lookup for BP4 but does not change the variant's out-of-scope status.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
BP5 VCEPNot applicable: ATM VCEP 1.5 prohibits BP5 because co-occurring pathogenic variants and similar phenotypes are recognized in this disease context. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.5 specification marks BP5 not applicable and instructs not to use it because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference, while ATM's lower penetrance increases the likelihood of co-occurring pathogenic variants. BP5 is therefore not assigned, regardless of the absence or presence of an alternate molecular basis in this case.

VCEP rule
Not applicable under ATM HBOP VCEP v1.5.
Evidence considered
  • ATM HBOP VCEP v1.5 marks BP5 not applicable and explicitly instructs not to use it in the ATM disease context.
Sources
cspec ↗
BP6 VCEPNot applicable: ATM VCEP 1.5 prohibits BP6, and ClinVar lists zero expert-panel submissions for this exact variant. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.5 specification marks BP6 not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. The exact ClinVar record also has zero expert-panel submissions, and no exact-variant expert-panel Benign or Likely benign classification is available. BP6 is therefore not assigned.

VCEP rule
Apply only to an exact-variant ClinVar expert-panel Benign or Likely benign classification; not applicable under ATM HBOP VCEP v1.5.
Evidence considered
  • ATM HBOP VCEP v1.5 states that BP6 is not applicable for this VCEP.
  • ClinVar exact-variant record reports expert-panel submissions: 0 and contains no expert-panel Benign or Likely benign classification.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: frameshift p.(Ser2764ArgfsTer4) is not a synonymous or qualifying deep-intronic variant within ATM VCEP BP7 scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_000051.4:c.8292_8293del is a frameshift variant producing p.(Ser2764ArgfsTer4), not a synonymous or qualifying deep-intronic variant. The ATM VCEP BP7 specification is restricted to synonymous and eligible deep-intronic variants, with optional RNA-based BP7 strength; it does not apply to frameshift variants. Therefore BP7 must not be evaluated.

Rule
ATM VCEP v1.5 BP7: synonymous or qualifying deep-intronic variants; BP7(RNA) may be weighted according to assay quality.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 specification restricts BP7 to synonymous and qualifying deep-intronic variants, with RNA-based BP7 strength options.
  • The variant is normalized as NM_000051.4:c.8292_8293del, p.(Ser2764ArgfsTer4), a frameshift consequence.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.8292_8293del
Protein (HGVS p.)
NP_000042.3:p.(Ser2764ArgfsTer4)
GRCh38
chr11:108343243 AGT>A
GRCh37
chr11:108213970 AGT>A
Location and type
Exon 57 · frameshift
ClinVar
245989

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 3 / 1,613,880 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 2 / 282,764 alleles AF 7.07e-06 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,613,880 alleles · 0 hom · FAF 6.8e-07
European (non-Finnish)3 / 1,179,934 2.5e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 7.1e-06 · 2 / 282,764 alleles · 0 hom
European (non-Finnish)2 / 129,112 1.5e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85887e-06; MAF= 0.00019%, 3/1613880 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54252e-06; MAF= 0.00025%, 3/1179934 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.07304e-06; MAF= 0.00071%, 2/282764 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.54904e-05; MAF= 0.00155%, 2/129112 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -21 bp
0.170
SpliceAI acceptor gainat -3 bp
0.068
SpliceAI donor lossat +128 bp
0.054
SpliceAI donor gainat -411 bp
0.000
Pangolin splice lossmagnitude shown
-0.061
Pangolin splice gain
0.107

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP PP3 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000051.4:c.8292_8293del is a frameshift variant producing p.(Ser2764ArgfsTer4), not a missense or splice-region/intronic variant. The ATM VCEP PP3 specification applies to missense variants through REVEL or to splicing variants through SpliceAI; therefore PP3 must not be evaluated for this protein-length-changing variant. The governing VCEP lookup file Suppl_TableS1_PMID 40580951.xlsx was searched for c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4, with no matching entry found.

Rule
ATM VCEP v1.5 PP3: missense REVEL >0.7333; splicing SpliceAI >=0.2.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 specification defines PP3 for missense variants using REVEL >0.7333 and for splicing variants using SpliceAI >=0.2; it does not make PP3 applicable to frameshift variants.
  • The variant is normalized as NM_000051.4:c.8292_8293del, p.(Ser2764ArgfsTer4), a frameshift consequence.
  • Suppl_TableS1_PMID 40580951.xlsx was searched under c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4; no matching row was found.
Still missing
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in Suppl_TableS1_PMID 40580951.xlsx; this file is a governing lookup for PP3 but does not change the variant's out-of-scope status.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
BP4 N/ANot applicable: frameshift p.(Ser2764ArgfsTer4) is outside ATM VCEP BP4 scope for missense or splice-region/intronic variants. Details ▾Hide ▴
Reasoning

Not applicable: NM_000051.4:c.8292_8293del is a frameshift variant producing p.(Ser2764ArgfsTer4), not a missense or splice-region/intronic variant. The ATM VCEP BP4 specification applies to missense variants through REVEL <=0.249 or to splicing variants through SpliceAI <=0.1; the case-specific policy also requires mechanism-appropriate evaluation and does not extend BP4 to truncating variants. Therefore BP4 must not be evaluated for this protein-length-changing variant. The governing VCEP lookup file Suppl_TableS1_PMID 40580951.xlsx was searched for c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4, with no matching entry found.

Rule
ATM VCEP v1.5 BP4: missense REVEL <=0.249; splicing SpliceAI <=0.1.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 specification defines BP4 for missense variants using REVEL <=0.249 or for splicing variants using SpliceAI <=0.1; it does not make BP4 applicable to frameshift variants.
  • The variant is normalized as NM_000051.4:c.8292_8293del, p.(Ser2764ArgfsTer4), a frameshift consequence.
  • Suppl_TableS1_PMID 40580951.xlsx was searched under c.8292_8293del, p.Ser2764ArgfsTer4, and p.S2764Rfs*4; no matching row was found.
Still missing
  • No entry for c.8292_8293del, p.Ser2764ArgfsTer4, or p.S2764Rfs*4 was found in Suppl_TableS1_PMID 40580951.xlsx; this file is a governing lookup for BP4 but does not change the variant's out-of-scope status.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
BP7 N/ANot applicable: frameshift p.(Ser2764ArgfsTer4) is not a synonymous or qualifying deep-intronic variant within ATM VCEP BP7 scope. Details ▾Hide ▴
Reasoning

Not applicable: NM_000051.4:c.8292_8293del is a frameshift variant producing p.(Ser2764ArgfsTer4), not a synonymous or qualifying deep-intronic variant. The ATM VCEP BP7 specification is restricted to synonymous and eligible deep-intronic variants, with optional RNA-based BP7 strength; it does not apply to frameshift variants. Therefore BP7 must not be evaluated.

Rule
ATM VCEP v1.5 BP7: synonymous or qualifying deep-intronic variants; BP7(RNA) may be weighted according to assay quality.
Evidence considered
  • The ClinGen HBOP ATM VCEP v1.5 specification restricts BP7 to synonymous and qualifying deep-intronic variants, with RNA-based BP7 strength options.
  • The variant is normalized as NM_000051.4:c.8292_8293del, p.(Ser2764ArgfsTer4), a frameshift consequence.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).

8 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.
    No paper-specific finding is recorded.
    PMID 27413114 ↗
  • Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
    No paper-specific finding is recorded.
    PMID 30348496 ↗
  • 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
    This study reports 12 novel ATM mutations in eight Chinese patients with ataxia-telangiectasia from six unrelated families, but the exact variant NM_000051.4:c.8292_8293del is not mentioned and no variant-specific segregation result is provided.
    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, paragraph 3

  • Ten new ATM alterations in Polish patients with ataxia-telangiectasia.
    Podralska MJ et al. · 2014
    This study reports ATM alterations in 24 unrelated Polish ataxia-telangiectasia families, but the exact variant NM_000051.4:c.8292_8293del is not mentioned and no variant-specific segregation result is provided.
    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, paragraph 1

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • Functional classification of ATM variants in ataxia-telangiectasia patients.
    Fiévet A et al. · 2019
    The paper functionally analyzes 49 ATM variants from 36 ataxia-telangiectasia patients using transcript, protein, phosphorylation, localization, and cell-cycle assays, but it does not explicitly mention the queried variant and its cohort-level findings cannot be assigned to it.
    Does not name this variant
    PMID 31050087 ↗
    Quoted passage
    The pathogenic effect of the 49 ATM variants highlighted by weak phosphorylation of KAP1 was therefore confirmed by the defective S-phase checkpoint.

    Results, section 4, Functional characterization of ATM variants, final paragraph

  • Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
    No paper-specific finding is recorded.
    PMID 34242744 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 3 / 1,613,880 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.170 Open source ↗
ClinVar 7 Pathogenic · 1 Likely 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

This variant is present in gnomAD v4.1 (AF= 1.85887e-06; MAF= 0.00019%, 3/1613880 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54252e-06; MAF= 0.00025%, 3/1179934 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.07304e-06; MAF= 0.00071%, 2/282764 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.54904e-05; MAF= 0.00155%, 2/129112 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (7 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 245989)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17).

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.