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ATMc.8735_8751delPathogenic
Print report
Variant interpretation report

ATM c.8735_8751del, p.(Arg2912AsnfsTer7)

NM_000051.4:c.8735_8751del NP_000042.3:p.(Arg2912AsnfsTer7) Frameshift · exon 60 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 v1.6. 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 at very strong: the 17-nucleotide deletion causes p.Arg2912AsnfsTer7, truncating ATM 139 residues before its 3057-residue normal length and upstream of the VCEP p.Arg3047 boundary.

PM2Supporting
PM2 · supporting

Met, supporting: the variant is absent from gnomAD v2.1 and v4.1, with observed frequency 0 versus the ATM VCEP PM2 threshold of <=0.001%.

PM5Supporting
PM5 · supporting

Met at supporting strength: the truncating product ends at approximately p.Asn2918, upstream of the ATM VCEP PM5 cutoff p.Leu3048, with PVS1 provisionally very strong.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: ATM VCEP Rule4 is met by PVS1 (very strong) plus PM2 and PM5 (supporting).

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
0.015 maximum delta

Recorded SpliceAI maximum delta score: 0.015. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.6, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 4 not met · 5 not assessed · 16 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 the requested codon, residue, and domain criteria, PS1, PM1, PP2, and BP1 are not applicable under the governing ATM VCEP framework.

PM5 is met at Supporting strength under the ATM truncation-cutoff rule, contingent on confirmation that PVS1 is finally assigned at Very Strong strength.

For ATM, the governing ClinGen HBOP VCEP Version 1.6 controls these criteria: PS2, PM6, and BS4 are not applicable, while PP1 is restricted to AR disease and requires documented affected-relative segregation.

No variant-specific segregation, de novo, parental-testing, phenotype, meiosis, or non-segregation data were available to support PP1.

The governing ATM VCEP v1.6 framework was used rather than generic ACMG defaults.

PS4 is not met because no qualifying exact-variant case-control enrichment or validated phenotype-count evidence was found.

PP4, BP5, and BP6 are not applicable under the ATM VCEP; PP5 is not met because the exact variant has no ClinVar Expert Panel Pathogenic or Likely pathogenic assertion.

Population evidence supports PM2 at Supporting strength because the variant is absent from the applicable gnomAD datasets.

BA1 and BS1 are not met because no population frequency is observed, and BS2 is not applicable under the ATM HBOP VCEP.

Met · 3

PVS1 Very strongMet at very strong: the 17-nucleotide deletion causes p.Arg2912AsnfsTer7, truncating ATM 139 residues before its 3057-residue normal length and upstream of the VCEP p.Arg3047 boundary. Details ▾Hide ▴
Reasoning

NM_000051.4:c.8735_8751del is a 17-nucleotide frameshift, normalized as NP_000042.3:p.(Arg2912AsnfsTer7), truncating ATM after predicted residue 2918 rather than preserving the normal 3057-residue protein. The ATM HBOP VCEP PVS1 specification recognizes frameshift variants as null-variant candidates, treats all exons of the default NM_000051.3 transcript as constitutive, and supports loss of function as a disease mechanism. The predicted termination is upstream of the VCEP's most 3-prime pathogenic boundary at p.Arg3047 and does not invoke a named VCEP downgrade for an extreme C-terminal event, non-critical exon, or an in-frame exon-skipping event. The variant therefore receives full-strength PVS1, recorded as the literal strength tier "very strong".

Rule
ATM HBOP VCEP PVS1 decision guide: full-strength PVS1 for an eligible null frameshift in the default constitutive transcript when no named downgrade rule applies.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8735_8751del as NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7), a frameshift with predicted protein position 2918 and normal protein length 3057.
  • The ATM HBOP VCEP PVS1 guide defines frameshift variants as null-variant candidates, states that all exons of the default NM_000051.3 transcript can be considered constitutive, and identifies loss of function as an established disease mechanism in the ATM framework.
  • The ATM VCEP guide states that the most 3-prime/C-terminal residue considered pathogenic is p.Arg3047; this truncation terminates at p.2918, upstream of that boundary.
  • SpliceAI max delta is 0.015, providing no indication that the consequence should be reinterpreted as a splice-altering event rather than the documented frameshift.
Still missing
  • The exact variant was not found in ATM_PVS1_1.5.pdf.txt under c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7; that file is a decision guide rather than a per-variant table.
Sources
cspec ↗vcep_atm_pvs1_1_5
PM2 SupportingMet, supporting: the variant is absent from gnomAD v2.1 and v4.1, with observed frequency 0 versus the ATM VCEP PM2 threshold of <=0.001%. Details ▾Hide ▴
Reasoning

The governing ATM HBOP VCEP version 1.6 applies PM2 at Supporting strength when frequency is <=0.001% in the gnomAD subpopulation with the highest frequency, with a single-observation exception. The variant is absent from gnomAD v2.1 and v4.1, including the reported non-cancer subsets, so its observed frequency is 0 and meets the threshold.

Rule
ATM HBOP VCEP v1.6: PM2 Supporting when frequency <=0.001% in the highest-frequency gnomAD subpopulation; a single observation confined to one subpopulation may also qualify.
Evidence considered
  • ATM HBOP VCEP version 1.6 specifies PM2 Supporting at frequency <=0.001% in the gnomAD subpopulation with the highest frequency, with a single-observation exception.
  • The variant is reported absent from gnomAD v2.1 and v4.1, and also absent from the available gnomAD v2.1 non-cancer and v3.1 non-cancer records; the observed allele frequency is therefore 0.
  • The VCEP does not require a non-cancer or exome-only source for PM2, so the default all-comers gnomAD entries were used for the primary assessment.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PM5 SupportingMet at supporting strength: the truncating product ends at approximately p.Asn2918, upstream of the ATM VCEP PM5 cutoff p.Leu3048, with PVS1 provisionally very strong. Details ▾Hide ▴
Reasoning

ATM VCEP v1.6 specifies PM5_Supporting for NMD-prone truncating DNA variants that receive PVS1 at Very Strong strength and create a premature termination codon upstream of p.Leu3048. This frameshift produces p.(R2912Nfs*7), terminating at approximately p.Asn2918, upstream of p.Leu3048; ATM loss of function is an established disease mechanism and the case PVS1 assessment supplies a very-strong default. The PVS1 artifact does not independently document the affected exon or final adjudicated PVS1 strength, so human confirmation is required before relying on this code clinically.

Rule
ATM VCEP v1.6 PM5_Supporting: apply to NMD-prone truncating DNA variants receiving PVS1 at Very Strong strength with a premature termination codon upstream of p.Leu3048.
Evidence considered
  • ATM VCEP v1.6 PM5 rule: DNA variants must be NMD-prone, truncating, receive PVS1 at Very Strong strength, and have a premature termination codon upstream of p.Leu3048; the assigned strength is Supporting.
  • The normalized protein consequence is p.(R2912Nfs*7), which predicts termination at approximately p.Asn2918 and therefore before p.Leu3048.
  • The gene-level PVS1 context identifies ATM loss of function as an established disease mechanism, and the variant-level assessment supplies a suggested default PVS1 strength of Very Strong.
Still missing
  • The available PVS1 assessment gives a suggested Very Strong strength but does not independently document the affected exon or a final adjudicated PVS1 strength; confirm these prerequisites.
Sources
cspec ↗pvs1_gene_contextpvs1_variant_assessment

Not met · 4 · evaluated, threshold not reached

PS4 Not met: no qualifying case-control p-value, effect estimate, confidence interval, or validated proband-count evidence was reported for this exact deletion. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 PS4 rule requires a case-control study with p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% confidence interval ≥1.5). No case-control cohort, affected-versus-control comparison, p-value, effect estimate, confidence interval, or validated proband-count evidence for NM_000051.4:c.8735_8751del was identified. Therefore the criterion is not met; no numeric comparison can be performed because no qualifying value is available.

Rule
Case-control studies; p-value ≤.05 and (Odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).
Evidence considered
  • The ATM VCEP v1.6 governing PS4 text states: 'Case-control studies; p-value ≤.05 and (Odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).'
  • The case evidence reports no ClinVar record and the fetched literature papers do not mention NM_000051.4:c.8735_8751del or p.(Arg2912AsnfsTer7); none provides a qualifying case-control estimate or affected-patient prevalence comparison.
Still missing
  • No variant-specific case-control study or validated multiple-unrelated-patient evidence with controls was available.
Sources
cspec ↗PMID:27413114 ↗PMID:30348496 ↗PMID:30553448 ↗
PP5 Not met: ClinVar contains no exact-variant expert-panel Pathogenic or Likely pathogenic classification for NM_000051.4:c.8735_8751del. Details ▾Hide ▴
Reasoning

PP5 requires an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic under the requested rule. The available ClinVar evidence reports no record, no variation ID, no classification, and no review status; therefore no expert-panel assertion exists to trigger PP5. Ordinary laboratory submissions, aggregate labels, and non-expert assertions do not qualify, and no such assertion was used.

Rule
Apply PP5 only for an exact-variant ClinVar Expert Panel classification of Pathogenic or Likely pathogenic; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • ClinVar search status was no_result; the case record states that this exact variant is absent from ClinVar, with empty classification, review-status, submission, and expert-panel fields.
  • Under the requested PP5 rule, only an exact-variant ClinVar Expert Panel Pathogenic or Likely pathogenic classification can trigger PP5; no such assertion is present.
Still missing
  • No exact-variant ClinVar expert-panel classification is available.
Sources
clinvar ↗
BA1 Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the ATM VCEP BA1 threshold of >0.5%. Details ▾Hide ▴
Reasoning

The governing ATM HBOP VCEP version 1.6 defines BA1 as a grpmax filtering allele frequency >0.5% in gnomAD. The variant is absent from the default all-comers gnomAD v2.1 and v4.1 datasets, so the BA1 threshold is not reached.

Rule
ATM HBOP VCEP v1.6: BA1 stand-alone when grpmax filtering AF >0.5% in gnomAD.
Evidence considered
  • ATM HBOP VCEP version 1.6 specifies BA1 at grpmax filtering AF >0.5% in gnomAD.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; no allele frequency or homozygote count is present.
  • The VCEP does not specify a non-cancer or exome-only source for BA1, so the default all-comers gnomAD entries were used.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: the variant is absent from gnomAD v2.1 and v4.1, below the ATM VCEP BS1 threshold of >0.05%. Details ▾Hide ▴
Reasoning

The governing ATM HBOP VCEP version 1.6 defines BS1 as a grpmax filtering allele frequency >0.05% in gnomAD. The variant is absent from the default all-comers gnomAD v2.1 and v4.1 datasets, so the BS1 threshold is not reached.

Rule
ATM HBOP VCEP v1.6: BS1 when grpmax filtering AF >0.05% in gnomAD.
Evidence considered
  • ATM HBOP VCEP version 1.6 specifies BS1 at grpmax filtering AF >0.05% in gnomAD.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; no allele frequency or homozygote count is present.
  • The VCEP does not specify a non-cancer or exome-only source for BS1, so the default all-comers gnomAD entries were used.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS3 Not assessed: no variant-specific result was found in the approved ATM functional assays, and the 17-base deletion is absent from the SNV functional table. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 specifies PS3 as Moderate when a variant fails to rescue both an ATM-specific feature and radiosensitivity, or Supporting when it fails to rescue an ATM-specific feature alone; the approved assay table requires confirmation that the variant was tested in the named Mitui 2009, Barone 2009, or Scott 2002 assays. Searches of clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx found no c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 entry, and the case literature extracts provide no variant-specific assay result. Suppl_TableS1_PMID 40580951 is a single-nucleotide-variant table and contains no entry for this 17-base deletion; therefore no calibrated PS3 strength can be assigned.

Rule
ATM VCEP v1.6 PS3: Supporting for failure to rescue an ATM-specific feature alone; Moderate for failure to rescue both an ATM-specific feature and radiosensitivity; do not use Strong. Apply only with confirmed variant-specific assay evidence.
Evidence considered
  • ATM VCEP v1.6 calibrates PS3 as Supporting for failure to rescue an ATM-specific feature alone and Moderate for failure to rescue both an ATM-specific feature and radiosensitivity; it says not to use PS3 Strong.
  • The approved ATM functional-assay table lists Mitui 2009 (PMID:18634022), Barone 2009 (PMID:19431188), and Scott 2002 (PMID:11805335) for kinase activity, with radiosensitivity add-on rules, but contains no row identifying this variant.
  • The Sun et al. 2025 table is explicitly keyed by SNV cHGVS nomenclature; searching all three supplied variant notations found no entry for this deletion.
  • The extracted PMID:27413114, PMID:30348496, and PMID:30553448 findings report no mention of this variant and no variant-specific assay result.
Still missing
  • No c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; this file is a methodology and calibration table, not a per-variant results table.
  • No c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 entry was found in Suppl_TableS1_PMID 40580951.xlsx; this table reports SNVs and does not provide a result for this deletion.
  • The case paper extracts for PMID:27413114, PMID:30348496, and PMID:30553448 do not mention this variant or provide a variant-specific ATM rescue assay result.
  • A primary-paper confirmation that this exact deletion was tested in an approved ATM kinase-activity assay, with its ATM-specific readout and any paired radiosensitivity result, is unavailable.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951PMID:27413114 ↗PMID:30348496 ↗PMID:30553448 ↗
PM3 Not assessed: no affected A-T proband, pathogenic variant in trans, phase information, or qualifying homozygous observation is documented for this variant. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM PM3/BP2 specification requires affected A-T proband observations with a pathogenic or likely pathogenic ATM variant in trans, or qualifying homozygous observations, scored by phenotype and phase. Searches of ATM_PM3_BP2_1.5.pdf.txt for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7 found no per-variant entry. The case evidence documents no affected A-T proband, pathogenic variant in trans, phase information, or qualifying homozygous observation for this variant. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, satisfying the specification's rarity prerequisite but providing no PM3 points. Therefore PM3 cannot be assessed.

Rule
PM3 points-based ATM VCEP rule: confident A-T phenotype = 4.0 confirmed in trans, 2.0 phase unknown, 1.0 second variant unidentified or VUS, 2.0 homozygous; consistent phenotype = half these values; PM3 Supporting = 1.0, Moderate = 2.0, Strong = 4.0, Very Strong = 8.0 points.
Evidence considered
  • The ATM VCEP PM3/BP2 table assigns PM3 points only from unrelated A-T probands: confident phenotype 4.0 confirmed in trans, 2.0 phase unknown, 1.0 second variant unidentified or VUS, or 2.0 for homozygosity; consistent phenotype receives half those values, with conversion at 1.0, 2.0, 4.0, and 8.0 points.
  • The governing ATM_PM3_BP2_1.5.pdf.txt was searched for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7; no entry was found.
  • The case evidence reports the variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the VCEP rarity prerequisite but supplying no affected-family or phase evidence.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in ATM_PM3_BP2_1.5.pdf.txt.
  • No affected A-T proband observation with phenotype classification is available.
  • No pathogenic or likely pathogenic ATM variant in trans, phase determination, or qualifying homozygous observation is available.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP1 Not assessed: zero affected relatives with documented segregation are available, below the ATM VCEP threshold of one affected relative for PP1 Supporting. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP Version 1.6 permits PP1 only for the autosomal-recessive A-T condition, with supporting strength for one affected relative, moderate for two, and strong for at least three. The available case evidence contains no documented affected relatives, parental segregation, phase, or meiosis data for this variant, so no PP1 strength can be assigned.

Rule
ATM VCEP Version 1.6: PP1 is applicable only for AR disease; Supporting = 1 affected relative, Moderate = 2, Strong = at least 3.
Evidence considered
  • The ATM VCEP allows PP1 for AR disease as Supporting with segregation in 1 affected relative, Moderate with 2 affected relatives, and Strong with at least 3 affected relatives.
  • No affected-relative segregation, parental phase, or meiosis data for NM_000051.4:c.8735_8751del are documented in the available case evidence.
Still missing
  • Documented testing and phenotype status of affected relatives are unavailable.
  • Parental phase and segregation results are unavailable.
  • No meiosis count or likelihood-based segregation analysis is available.
Sources
cspec ↗
BS3 Not assessed: no variant-specific benign functional result was found in the approved ATM assays, and the 17-base deletion is absent from the SNV functional table. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 specifies BS3 as Supporting when a variant rescues either an ATM-specific feature or radiosensitivity, and Moderate when it rescues both; the approved assay table requires confirmation that the variant was tested in the named assays. Searches of clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx found no c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 entry, and the case literature extracts provide no variant-specific benign functional result. Suppl_TableS1_PMID 40580951 is a single-nucleotide-variant table and contains no entry for this 17-base deletion; therefore no calibrated BS3 strength can be assigned.

Rule
ATM VCEP v1.6 BS3: Supporting for rescue of either an ATM-specific feature or radiosensitivity; Moderate for rescue of both. Apply only with confirmed variant-specific assay evidence.
Evidence considered
  • ATM VCEP v1.6 calibrates BS3 as Supporting for rescue of either an ATM-specific feature or radiosensitivity and Moderate for rescue of both.
  • The approved ATM functional-assay table lists the calibrated kinase-activity and radiosensitivity methodologies but contains no row identifying this variant or reporting a benign result for it.
  • The Sun et al. 2025 table is explicitly keyed by SNV cHGVS nomenclature; searching all three supplied variant notations found no entry for this deletion.
  • The extracted PMID:27413114, PMID:30348496, and PMID:30553448 findings report no mention of this variant and no variant-specific benign functional result.
Still missing
  • No c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; this file is a methodology and calibration table, not a per-variant results table.
  • No c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 entry was found in Suppl_TableS1_PMID 40580951.xlsx; this table reports SNVs and does not provide a result for this deletion.
  • The case paper extracts for PMID:27413114, PMID:30348496, and PMID:30553448 do not mention this variant or provide a variant-specific benign functional assay result.
  • A primary-paper confirmation that this exact deletion was tested in an approved ATM assay and rescued an ATM-specific feature or radiosensitivity is unavailable.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1vcep_suppl_tables1_pmid_40580951PMID:27413114 ↗PMID:30348496 ↗PMID:30553448 ↗
BP2 Not assessed: no unaffected adult carrier with a pathogenic or likely pathogenic ATM variant in trans, phase, or setting is documented. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM PM3/BP2 specification requires an unaffected non-A-T adult carrying the assessed variant with a pathogenic or likely pathogenic ATM variant in trans, with phase and setting determining the negative point value; observations in cis must not be used. Searches of ATM_PM3_BP2_1.5.pdf.txt for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7 found no per-variant entry. The case evidence contains no unaffected adult carrier, pathogenic or likely pathogenic variant in trans, phase information, or laboratory/database setting for this variant. Therefore BP2 cannot be assessed.

Rule
BP2 points-based ATM VCEP rule: unaffected non-A-T adult with a pathogenic or likely pathogenic variant in trans = -4.0 confirmed in trans or -2.0 phase unknown; homozygous = -2.0 laboratory setting or -1.0 database setting; BP2 Supporting = -1.0, Moderate = -2.0, Strong = <= -4.0 points.
Evidence considered
  • The ATM VCEP BP2 table assigns negative points only for unaffected non-A-T adults carrying the assessed variant with a pathogenic or likely pathogenic ATM variant: -4.0 confirmed in trans, -2.0 phase unknown, or homozygous -2.0 in a laboratory setting and -1.0 in a database setting; observations used for frequency codes are excluded.
  • The governing ATM_PM3_BP2_1.5.pdf.txt was searched for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7; no entry was found.
  • The case evidence contains no unaffected adult carrier, pathogenic or likely pathogenic ATM variant in trans, phase information, or laboratory/database setting for this variant.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in ATM_PM3_BP2_1.5.pdf.txt.
  • No unaffected non-A-T adult carrier observation is available.
  • No pathogenic or likely pathogenic ATM variant in trans, phase determination, or laboratory/database setting is available.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: ATM VCEP PS1 covers missense or splice-region variants, whereas this variant is a frameshift producing p.Arg2912AsnfsTer7. Details ▾Hide ▴
Reasoning

The governing ATM VCEP PS1 specification is restricted to missense variants with the same amino-acid change or to splice-region variants meeting its splice-event comparison table. NM_000051.4:c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), so neither PS1 path applies. Searches of ATM_PS1_1.5.pdf for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7 found no variant-specific entry.

Rule
ATM VCEP PS1: use for missense changes when splicing is ruled out, or use the ATM PS1 Splicing table for splice variants with similar predictions or observations.
Evidence considered
  • ATM VCEP v1.6 marks PS1 as applicable to missense changes or splice variants evaluated with the ATM PS1 Splicing table.
  • The normalized consequence is frameshift with protein consequence NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7).
  • The complete ATM_PS1_1.5.pdf text was searched under all three requested variant notations and contained no variant-specific entry.
Still missing
  • No variant-specific entry was found in ATM_PS1_1.5.pdf for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7.
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 VCEPNot applicable: the ATM VCEP excludes PS2 for both autosomal-dominant and autosomal-recessive disease because informative de novo occurrences are not established. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP Version 1.6 specifies that PS2 is not applicable for ATM autosomal-dominant or autosomal-recessive disease because informative de novo occurrences have not been observed and de novo evidence is not informative for the recessive condition.

VCEP rule
ATM VCEP Version 1.6: PS2 not applicable; do not use for AD or AR disease.
Evidence considered
  • The governing ATM VCEP Version 1.6 labels PS2 not applicable for AD and AR disease and instructs not to use it because informative de novo occurrences have not been observed.
Sources
cspec ↗
PM1 VCEPNot applicable: ATM VCEP v1.6 marks PM1 as not applicable, and this frameshift is not a missense change assessed by a critical-domain rule. Details ▾Hide ▴
Reasoning

The governing ATM VCEP v1.6 framework explicitly marks PM1 as Not Applicable. The authoritative vcep_materials.json domain_tables object has no ATM entry, and this frameshift is not a missense residue substitution for which a critical functional domain assessment would establish PM1.

VCEP rule
ATM VCEP v1.6: PM1 applicability is Not Applicable.
Evidence considered
  • ATM VCEP v1.6 lists PM1 as Not Applicable.
  • The authoritative domain_tables object in vcep_materials.json contains no ATM entry.
  • The variant is a frameshift, not a missense substitution requiring residue-to-domain mapping.
Sources
cspec ↗
PM4 N/ANot applicable: ATM VCEP PM4 is reserved for stop-loss variants, whereas this variant is a frameshift producing a premature stop at p.Asn2918. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP specifies PM4 for stop-loss variants. This variant is a frameshift that creates a premature termination codon, not a stop-loss or other in-frame protein-length change; therefore PM4 is not applicable.

Rule
ATM HBOP VCEP PM4: use for stop-loss variants.
Evidence considered
  • The ATM VCEP criterion specification states PM4: use for stop-loss variants.
  • The case normalization classifies NM_000051.4:c.8735_8751del as a frameshift, p.(Arg2912AsnfsTer7), rather than a stop-loss variant.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP excludes PM6 for both autosomal-dominant and autosomal-recessive disease because assumed de novo evidence is not informative. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP Version 1.6 specifies that PM6 is not applicable for ATM autosomal-dominant or autosomal-recessive disease because assumed de novo observations are not informative for these disease contexts.

VCEP rule
ATM VCEP Version 1.6: PM6 not applicable; do not use for AD or AR disease.
Evidence considered
  • The governing ATM VCEP Version 1.6 labels PM6 not applicable for AD and AR disease and instructs not to use it because informative de novo occurrences have not been observed.
Sources
cspec ↗
PP2 VCEPNot applicable: ATM VCEP v1.6 explicitly marks PP2 as not applicable for this gene framework. Details ▾Hide ▴
Reasoning

The governing ATM VCEP v1.6 framework explicitly marks PP2 as Not Applicable. This criterion therefore cannot be applied, regardless of the variant's consequence or ATM missense mechanism.

VCEP rule
ATM VCEP v1.6: PP2 applicability is Not Applicable.
Evidence considered
  • ATM VCEP v1.6 lists PP2 as Not Applicable.
Sources
cspec ↗
PP3 N/ANot applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), outside PP3's calibrated missense or splicing scope. Details ▾Hide ▴
Reasoning

PP3 is not applicable. The variant is a frameshift, NM_000051.4:c.8735_8751del, producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7). Under the ATM VCEP Version 1.6 framework, PP3 is calibrated for missense variants through REVEL or for silent, missense/in-frame, and intronic variants through the specified splicing path; this truncating, protein-length-changing variant is outside the criterion's scope. Accordingly, no SpliceAI, REVEL, or other computational predictor was used to evaluate PP3. The on-record Suppl_TableS1_PMID 40580951.xlsx full-text table was searched for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7, with no variant-specific entry found.

Rule
ATM VCEP Version 1.6 PP3: missense REVEL >.7333; splicing SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8735_8751del as a frameshift producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7).
  • ATM VCEP Version 1.6 assigns PP3 to calibrated missense REVEL evidence or specified splicing evidence for silent, missense/in-frame, and intronic variants; a frameshift is outside this scope.
  • The full-text Suppl_TableS1_PMID 40580951.xlsx was searched under all three supplied variant notations and no matching entry was found.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in Suppl_TableS1_PMID 40580951.xlsx; this does not change the out-of-scope determination.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
PP4 VCEPNot applicable: the ATM VCEP prohibits separate PP4 use because cancer is genetically heterogeneous and ataxia-telangiectasia phenotype is incorporated into PM3/BP2. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 marks PP4 not applicable. For ATM-related cancer predisposition, hereditary and sporadic breast cancer have substantial genetic heterogeneity; for autosomal-recessive ataxia-telangiectasia, phenotype evidence is incorporated into the ATM PM3/BP2 points framework rather than used as a separate PP4 line of evidence.

VCEP rule
PP4 is not applicable under ATM VCEP v1.6 for both the autosomal-dominant cancer and autosomal-recessive ataxia-telangiectasia contexts.
Evidence considered
  • The ATM VCEP v1.6 PP4 instructions state: 'Autosomal Dominant: do not use as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes.'
  • The same instructions state: 'Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3|BP2 table.'
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM HBOP VCEP version 1.6 explicitly designates BS2 as not applicable. Details ▾Hide ▴
Reasoning

The governing ATM HBOP VCEP version 1.6 explicitly marks BS2 as not applicable. No BS2 assessment is therefore made, regardless of the absence of the variant from population datasets.

VCEP rule
ATM HBOP VCEP v1.6: BS2 not applicable.
Evidence considered
  • ATM HBOP VCEP version 1.6 lists BS2 as Not Applicable.
  • No unaffected-carrier or homozygote observation is used because the governing VCEP excludes this criterion.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP assigns no BS4 weight because informative non-segregation is too rare in A-T and low penetrance confounds AD segregation. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP Version 1.6 labels BS4 not applicable. For the AR A-T condition, the VCEP states that informative lack-of-segregation instances are too rare to receive weight; for the AD condition, the VCEP cautions that low penetrance can produce false-positive non-segregation results.

VCEP rule
ATM VCEP Version 1.6: BS4 not applicable; AR non-segregation is too rare for weight and AD low penetrance confounds segregation analysis.
Evidence considered
  • The governing ATM VCEP Version 1.6 labels BS4 not applicable and states that informative lack-of-segregation instances in A-T are too rare to receive weight.
  • The ATM VCEP cautions that co-segregation analysis in low-penetrance AD disease can produce false-positive results.
Sources
cspec ↗
BP1 VCEPNot applicable: ATM VCEP v1.6 explicitly marks BP1 as not applicable for this gene framework. Details ▾Hide ▴
Reasoning

The governing ATM VCEP v1.6 framework explicitly marks BP1 as Not Applicable. This criterion therefore cannot be applied to the current frameshift variant.

VCEP rule
ATM VCEP v1.6: BP1 applicability is Not Applicable.
Evidence considered
  • ATM VCEP v1.6 lists BP1 as Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: ATM VCEP marks BP3 as unavailable, and this variant is a truncating frameshift rather than an in-frame repeat-region deletion. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP marks BP3 as not applicable. Independently, BP3 is intended for in-frame deletions or insertions in a repetitive region without a predicted functional effect, whereas this variant is a protein-truncating frameshift with a premature termination codon.

VCEP rule
ATM HBOP VCEP BP3: Not Applicable.
Evidence considered
  • The ATM HBOP VCEP criterion specification lists BP3 as Not Applicable.
  • The case normalization classifies the 17-nucleotide deletion as a frameshift producing p.(Arg2912AsnfsTer7), not an in-frame repeat-region deletion.
Sources
cspec ↗
BP4 N/ANot applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), outside BP4's calibrated missense, intronic, synonymous, or splice-region scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable. The variant is a frameshift, NM_000051.4:c.8735_8751del, producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7). Under the governing scope rule, BP4 applies only to missense variants through REVEL or to intronic, synonymous, or splice-region variants through SpliceAI; a frameshift is outside the criterion's calibrated scope. Therefore the available SpliceAI max delta of 0.015 was not evaluated as BP4 evidence, and REVEL was not applicable. The on-record Suppl_TableS1_PMID 40580951.xlsx full-text table was searched for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7, with no variant-specific entry found.

Rule
ATM VCEP Version 1.6 BP4: missense REVEL <=.249; splicing no predicted impact via SpliceAI <=0.1.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8735_8751del as a frameshift producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7).
  • ATM VCEP Version 1.6 BP4 calibration covers missense REVEL <=.249 or splicing SpliceAI <=0.1; the governing scope instruction excludes truncating variants from this computational criterion.
  • SpliceAI reports max delta 0.015, but this score was not used because the variant is a frameshift and BP4 is upstream not_applicable.
  • The full-text Suppl_TableS1_PMID 40580951.xlsx was searched under all three supplied variant notations and no matching entry was found.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in Suppl_TableS1_PMID 40580951.xlsx; this does not change the out-of-scope determination.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951
BP5 VCEPNot applicable: the ATM VCEP v1.6 explicitly designates BP5 as not applicable for this gene and disease framework. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 marks BP5 not applicable. No BP5 evidence was applied, and no numeric BP5 comparison is available or required under this governing framework.

VCEP rule
BP5 is not applicable under ATM VCEP v1.6.
Evidence considered
  • The ATM VCEP v1.6 criterion table lists BP5 as 'Not applicable.'
Sources
cspec ↗
BP6 VCEPNot applicable: ATM VCEP v1.6 prohibits BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 marks BP6 not applicable and states that it is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Independently, the exact variant is absent from ClinVar, so there is no exact-variant ClinVar expert-panel Benign or Likely benign classification that could trigger BP6 under the requested rule.

VCEP rule
BP6 is not applicable under ATM VCEP v1.6; if considered under the requested general gate, apply only for an exact-variant ClinVar Expert Panel classification of Benign or Likely benign.
Evidence considered
  • The ATM VCEP v1.6 BP6 instructions state: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.'
  • ClinVar search status was no_result, with no exact-variant classification, review status, submission, or expert-panel assertion available.
  • Under the requested BP6 rule, only an exact-variant ClinVar Expert Panel Benign or Likely benign classification can trigger BP6; none exists.
Sources
cspec ↗clinvar ↗
BP7 N/ANot applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), not a synonymous or qualifying deep-intronic variant for BP7. Details ▾Hide ▴
Reasoning

BP7 is not applicable. The variant is a frameshift, NM_000051.4:c.8735_8751del, producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7), not a synonymous substitution. The ATM VCEP Version 1.6 BP7 rule is limited to synonymous and qualifying deep intronic variants, with separate RNA-based provisions; a frameshift is outside that scope. Accordingly, no SpliceAI score or RNA evidence was evaluated for BP7. Searches of the on-record ATM VCEP full-text files for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7 found no variant-specific entry.

Rule
ATM VCEP Version 1.6 BP7: synonymous and deep intronic variants beyond +7 and -21 at donor and acceptor sites, respectively; RNA provisions apply when observed RNA evidence is available.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8735_8751del as a frameshift producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7).
  • ATM VCEP Version 1.6 limits BP7 to synonymous and qualifying deep intronic variants, with optional RNA-based evidence; a frameshift is outside this scope.
  • The on-record ATM VCEP full-text files were searched under all three supplied variant notations and no matching entry was found.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in the searched on-record ATM VCEP full-text files; this does not change the out-of-scope determination.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.8735_8751del
Protein (HGVS p.)
NP_000042.3:p.(Arg2912AsnfsTer7)
GRCh38
chr11:108353828 AGAGATATTGTGGATGGC>A
GRCh37
chr11:108224555 AGAGATATTGTGGATGGC>A
Location and type
Exon 60 · frameshift

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 -62 bp
0.005
SpliceAI acceptor gainat -45 bp
0.010
SpliceAI donor lossat -167 bp
0.015
SpliceAI donor gainat -200 bp
0.000
Pangolin splice lossmagnitude shown
-0.055
Pangolin splice gain
0.004

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), outside PP3's calibrated missense or splicing scope. Details ▾Hide ▴
Reasoning

PP3 is not applicable. The variant is a frameshift, NM_000051.4:c.8735_8751del, producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7). Under the ATM VCEP Version 1.6 framework, PP3 is calibrated for missense variants through REVEL or for silent, missense/in-frame, and intronic variants through the specified splicing path; this truncating, protein-length-changing variant is outside the criterion's scope. Accordingly, no SpliceAI, REVEL, or other computational predictor was used to evaluate PP3. The on-record Suppl_TableS1_PMID 40580951.xlsx full-text table was searched for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7, with no variant-specific entry found.

Rule
ATM VCEP Version 1.6 PP3: missense REVEL >.7333; splicing SpliceAI >=0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8735_8751del as a frameshift producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7).
  • ATM VCEP Version 1.6 assigns PP3 to calibrated missense REVEL evidence or specified splicing evidence for silent, missense/in-frame, and intronic variants; a frameshift is outside this scope.
  • The full-text Suppl_TableS1_PMID 40580951.xlsx was searched under all three supplied variant notations and no matching entry was found.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in Suppl_TableS1_PMID 40580951.xlsx; this does not change the out-of-scope determination.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951
BP4 N/ANot applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), outside BP4's calibrated missense, intronic, synonymous, or splice-region scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable. The variant is a frameshift, NM_000051.4:c.8735_8751del, producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7). Under the governing scope rule, BP4 applies only to missense variants through REVEL or to intronic, synonymous, or splice-region variants through SpliceAI; a frameshift is outside the criterion's calibrated scope. Therefore the available SpliceAI max delta of 0.015 was not evaluated as BP4 evidence, and REVEL was not applicable. The on-record Suppl_TableS1_PMID 40580951.xlsx full-text table was searched for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7, with no variant-specific entry found.

Rule
ATM VCEP Version 1.6 BP4: missense REVEL <=.249; splicing no predicted impact via SpliceAI <=0.1.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8735_8751del as a frameshift producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7).
  • ATM VCEP Version 1.6 BP4 calibration covers missense REVEL <=.249 or splicing SpliceAI <=0.1; the governing scope instruction excludes truncating variants from this computational criterion.
  • SpliceAI reports max delta 0.015, but this score was not used because the variant is a frameshift and BP4 is upstream not_applicable.
  • The full-text Suppl_TableS1_PMID 40580951.xlsx was searched under all three supplied variant notations and no matching entry was found.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in Suppl_TableS1_PMID 40580951.xlsx; this does not change the out-of-scope determination.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951
BP7 N/ANot applicable: ATM c.8735_8751del is a frameshift producing p.(Arg2912AsnfsTer7), not a synonymous or qualifying deep-intronic variant for BP7. Details ▾Hide ▴
Reasoning

BP7 is not applicable. The variant is a frameshift, NM_000051.4:c.8735_8751del, producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7), not a synonymous substitution. The ATM VCEP Version 1.6 BP7 rule is limited to synonymous and qualifying deep intronic variants, with separate RNA-based provisions; a frameshift is outside that scope. Accordingly, no SpliceAI score or RNA evidence was evaluated for BP7. Searches of the on-record ATM VCEP full-text files for c.8735_8751del, p.Arg2912AsnfsTer7, and p.R2912Nfs*7 found no variant-specific entry.

Rule
ATM VCEP Version 1.6 BP7: synonymous and deep intronic variants beyond +7 and -21 at donor and acceptor sites, respectively; RNA provisions apply when observed RNA evidence is available.
Evidence considered
  • The case normalization identifies NM_000051.4:c.8735_8751del as a frameshift producing NP_000042.3:p.(Arg2912AsnfsTer7) / p.(R2912Nfs*7).
  • ATM VCEP Version 1.6 limits BP7 to synonymous and qualifying deep intronic variants, with optional RNA-based evidence; a frameshift is outside this scope.
  • The on-record ATM VCEP full-text files were searched under all three supplied variant notations and no matching entry was found.
Still missing
  • No entry for c.8735_8751del, p.Arg2912AsnfsTer7, or p.R2912Nfs*7 was found in the searched on-record ATM VCEP full-text files; this does not change the out-of-scope determination.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • ATM Mutations in Cancer: Therapeutic Implications.
    The paper does not explicitly mention ATM c.8735_8751del or NP_000042.3:p.(R2912Nfs*7). It reports that ATM mutations in cancer span the gene and that the functional impact of each individual somatic ATM mutation is not established, so it provides no variant-specific functional result for this deletion.
    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.

    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 report the ATM c.8735_8751del variant or NP_000042.3:p.(R2912Nfs*7). It investigates ATM loss and a catalytically inactive ATM allele in mouse central nervous system and Purkinje cells, reporting effects on double-strand-break repair but no result for this deletion.
    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 (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, paragraph 2

  • Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
    The paper does not report ATM c.8735_8751del or p.(R2912Nfs*7). It examines ATM deficiency or loss of ATM kinase activity in human fibroblasts and finds increased reactive oxygen species, active Rac1, cellular spreading, and migration, but no variant-specific functional result for this deletion.
    Does not name this variant
    PMID 30553448 ↗
    Quoted passage
    Here we show that loss of ATM kinase activity elevates intracellular ROS, leading to Rac1 activation. Rac1 activity drives cytoskeletal rearrangements resulting in increased cellular spreading and motility. Rac1 siRNA or treatment with the ROS scavenger N-Acetyl-L-cysteine restores wild-type migration.

    Abstract; Results sections 3.1–3.4

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 0.015 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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.