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ATMc.8287C>TPathogenic
Print report
Variant interpretation report

ATM c.8287C>T, p.Arg2763Ter

NM_000051.4:c.8287C>T NP_000042.3:p.(Arg2763Ter) Nonsense · exon 57 View identifiers
Classification
Pathogenic

Variant description:

The ATM NM_000051.4:c.8287C>T (NP_000042.3:p.(Arg2763Ter)) nonsense variant has previously been reported in somatic cancers (COSMIC; COSV53734668, n = 6 times). This variant is predicted to result in an absent or disrupted protein product. Experimental evidence: Direct prime-editing Table S1 measurement classified c.8287C>T as Non-functional with High confidence and DeepATM_predicted=No. Based on available guidelines, this variant is considered to be Pathogenic.

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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong

Met at very strong: the exon-57 nonsense p.Arg2763Ter falls within the VCEP's NMD-predicted p.Ser2_Glu2979 interval.

PS3Supporting
PS3 · supporting

Met, Supporting: direct prime-editing Table S1 measurement classified c.8287C>T as Non-functional with High confidence and DeepATM_predicted=No.

PM2Supporting
PM2 · supporting

Met at supporting: the highest gnomAD v4.1 subpopulation AF is 0.000339%, below the VCEP's <=0.001% PM2 threshold.

PM3Moderate
PM3 · moderate

Met at Moderate: one confident A-T proband with a phase-unknown second truncating ATM variant contributes 2.0 PM3 points, meeting the VCEP Moderate threshold.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: ATM VCEP Rule4 is satisfied by PVS1 very strong plus PS3 and PM2 supporting, with additional PM3 moderate evidence.

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
0.149 maximum delta

Recorded SpliceAI maximum delta score: 0.149. Refer to the recorded PP3/BP4 rationale for interpretation.

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

8 Pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
6 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53734668, n = 6 times).

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: 4 met · 2 not met · 5 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

Only PS4 is applicable among these five criteria; the available literature documents affected patients but not the VCEP-required case-control statistics.

PP4, PP5, BP5, and BP6 are explicitly not applicable under the ATM VCEP v1.6 rules.

All three requested criteria are not applicable because the variant is a nonsense substitution and lies outside the governing VCEP scope for PP3, BP4, and BP7 as applied here.

The exact c.8287C>T row was found in the governing Sun et al. 2025 Supplementary Table S1; no pre-assigned PP3 or BP4 code is present for this nonsense row.

Met · 4

PVS1 Very strongVCEPMet at very strong: the exon-57 nonsense p.Arg2763Ter falls within the VCEP's NMD-predicted p.Ser2_Glu2979 interval. Details ▾Hide ▴
Reasoning

NM_000051.4:c.8287C>T is a nonsense variant producing NP_000042.3:p.(Arg2763Ter) / p.(R2763*), in the clinically relevant ATM transcript. The VCEP identifies nonsense variants predicted to undergo NMD through p.Ser2_Glu2979 as full-strength PVS1. This stop codon at p.Arg2763 lies within that NMD-predicted interval, well before the terminal region, and the VCEP states that the ATM transcript exons are constitutive without major rescue isoforms. The variant-level assessment identifies exon 57 and a nonsense consequence; therefore the governing VCEP rule supports PVS1 at very strong strength without a downgrade. The exact variant was also reported as c.8287C>T / p.Arg2763X in Table 2 of Cavalieri et al. (PMID:17910737).

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease ... Nonsense or frameshift | Predicted to undergo NMD (p.Ser2_Glu2979) | PVS1
Evidence considered
  • VCEP PVS1 guide: nonsense or frameshift variants predicted to undergo NMD through p.Ser2_Glu2979 receive PVS1; the guide also states that all exons of the default ATM transcript can be considered constitutive without major alternative splice isoforms that could rescue presumed loss-of-function events.
  • Case variant assessment: NM_000051.4:c.8287C>T, NP_000042.3:p.(Arg2763Ter) / p.(R2763*), exon 57, consequence class nonsense.
  • Cavalieri et al. 2008, Table 2, mutation entry for exon 59: patient AT43TO, c.8287C>T, p.Arg2763X, reported as a nonsense mutation predicted to cause protein truncation.
Still missing
  • No exact c.8287C>T, p.Arg2763Ter, or p.R2763* entry was found in ATM_PVS1_1.6.pdf.txt; the VCEP decision-tree rule was applied to the documented variant consequence and position.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗pvs1_variant_assessmentPMID:17910737 ↗
PS3 SupportingVCEPMet, Supporting: direct prime-editing Table S1 measurement classified c.8287C>T as Non-functional with High confidence and DeepATM_predicted=No. Details ▾Hide ▴
Reasoning

The exact Table S1 row for c.8287C>T (p.R2763*) reports Classification=Non-functional, Confidence=High, and DeepATM_predicted=No. Under the governing VCEP file policy, this is a direct prime-editing measurement, and a non-functional result supports PS3 at Supporting strength. The approved ATM assay calibration file was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; it contains methodology and strength thresholds but no variant-specific result. The variant-specific functional evidence therefore comes from the direct prime-editing row, not from the mere presence of PS3 text in the assay-calibration table.

VCEP rule
Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency
Evidence considered
  • Sun et al. 2025, Supplementary Table S1, row hg38 108343240 C>T / ATM c.8287C>T / R2763*: Variant_consequence=Nonsense; Classification=Non-functional; Confidence=High; DeepATM_predicted=No; Combined_score=-5.08084184988672.
  • The VCEP's ATM functional assay calibration file was searched for c.8287C>T, p.Arg2763Ter, and p.R2763* and returned no variant-specific result; it describes approved assay methodology and proposed strength calibration only.
Still missing
  • The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched under c.8287C>T, p.Arg2763Ter, and p.R2763*; no variant-specific entry was found, so its approved-assay calibration cannot independently add weight.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PM2 SupportingVCEPMet at supporting: the highest gnomAD v4.1 subpopulation AF is 0.000339%, below the VCEP's <=0.001% PM2 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PM2 at Supporting strength when the frequency is <=0.001% in the gnomAD subpopulation with the highest frequency, with a stated exception for a singleton confined to one subpopulation. In gnomAD v4.1, the highest observed subpopulation frequency is European (non-Finnish) AF 3.39012e-06 (0.000339%; 4/1,179,898 alleles; 0 homozygotes), which is <=0.001%; therefore PM2_Supporting is met.

VCEP rule
Frequency **≤.001%** in gnomAD subpopulation with the highest frequency Exception: If >0.001% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2\_supporting would apply.
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC PM2 rule: Frequency <=.001% in gnomAD subpopulation with the highest frequency; exception for >0.001% but n=1 in a single subpopulation not present in any other subpopulation.
  • gnomAD v4.1 all-comers result for NM_000051.4:c.8287C>T: highest observed subpopulation is European (non-Finnish), AF 3.39012e-06 (0.000339%), 4/1,179,898 alleles, homozygotes 0; grpmax FAF 7.9e-07.
Sources
cspec ↗gnomad_v4 ↗
PM3 ModerateVCEPMet at Moderate: one confident A-T proband with a phase-unknown second truncating ATM variant contributes 2.0 PM3 points, meeting the VCEP Moderate threshold. Details ▾Hide ▴
Reasoning

The VCEP ATM PM3/BP2 table assigns 2.0 points to an unrelated A-T proband with a confident phenotype when the assessed variant is in phase-unknown configuration with a pathogenic or likely pathogenic second variant. Patient AT43TO had progressive ataxia and elevated AFP, meeting the VCEP confident-phenotype path (clinical feature 1a plus laboratory result 2). The patient carried c.8287C>T as the second allele and c.5932G>T (p.Glu1978X), a truncating ATM variant, as the first allele; the paper does not document parental genotyping or otherwise confirm phase, so the phase-unknown column applies. The VCEP threshold maps 2.0 points to PM3 Moderate. The VCEP PM3/BP2 file was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; it contains no variant-specific row, so the governing answer comes from its pre-assigned points table rather than a variant row.

VCEP rule
PM3 For recessive disorders, detected in trans with a pathogenic variant ... CONFIDENT PHENOTYPE (must include Laboratory result) ... Presence of Clinical feature 1a or 1b AND presence of Laboratory result 1 or 2 ... Phenotype confident 4.0 2.0 1.0 2.0 ... PM3 = 2 points
Evidence considered
  • Porcedda et al. 2008, PMID:18431795, Table 2 and Results: AT43TO had ataxia and increased AFP; the paper classified AT43TO among the A-T patients.
  • Porcedda et al. 2008, PMID:18431795, Table 3: AT43TO carried c.5932G>T; c.8287C>T and had c-H2AX mean fluorescence 7.30 in T-cell lines and 9.10 in PBMCs, below the paper's A-T thresholds.
  • Cavalieri et al. 2008, PMID:17910737, Table 2: c.5932G>T (p.Glu1978X) is labeled the first allele in AT43TO and c.8287C>T (p.Arg2763X) the second allele; no parental phase confirmation is reported.
  • ATM_PM3_BP2_1.6.pdf Ataxia Telangiectasia PM3|BP2 table: a confident phenotype with phase unknown contributes 2.0 points when the second variant is pathogenic/likely pathogenic. The VCEP criterion mapping states PM3 = 2 points for Moderate; the case therefore contributes 2.0 PM3 points.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; no variant-specific entry was found.
  • Parental genotyping or other direct phase testing for AT43TO was not reported; therefore the phase-unknown, not confirmed-in-trans, column was used.
Sources
vcep_atm_pm3_bp2_1_6 ↗cspec ↗PMID:17910737 ↗PMID:18431795 ↗

Not met · 2 · evaluated, threshold not reached

BA1 VCEPNot met: gnomAD v4.1 grpmax FAF is 0.000079%, below the VCEP's >0.5% BA1 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP requires BA1 when the gnomAD group-maximum filtering allele frequency is >0.5%. gnomAD v4.1 reports grpmax FAF 7.9e-07 (0.000079%), far below 0.5%; therefore BA1 is not met.

VCEP rule
Grpmax Filtering AF **>.5%** in gnomAD
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BA1 rule: Grpmax Filtering AF >.5% in gnomAD.
  • gnomAD v4.1 all-comers result for NM_000051.4:c.8287C>T: total AF 2.47868e-06, 4/1,613,760 alleles, homozygotes 0; grpmax FAF 7.9e-07 (0.000079%).
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax FAF is 0.000079%, below the VCEP's >0.05% BS1 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP requires BS1 when the gnomAD group-maximum filtering allele frequency is >0.05%. gnomAD v4.1 reports grpmax FAF 7.9e-07 (0.000079%), below 0.05%; therefore BS1 is not met.

VCEP rule
Grpmax Filtering AF **>.05%** in gnomAD
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BS1 rule: Grpmax Filtering AF >.05% in gnomAD.
  • gnomAD v4.1 all-comers result for NM_000051.4:c.8287C>T: grpmax FAF 7.9e-07 (0.000079%); highest observed subpopulation was European (non-Finnish), AF 3.39012e-06 (0.000339%), with 4/1,179,898 alleles and 0 homozygotes.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS4 VCEPNot assessed: patient reports document c.8287C>T in A-T cases but provide no control counts or p-value needed for the VCEP's PS4 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP requires a case-control study with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥2 or a lower 95% CI ≥1.5. The reviewed reports for NM_000051.4:c.8287C>T document the variant in individual A-T patients, including AT43TO, but provide no unaffected or population-control comparison counts, p-value, odds ratio, hazard ratio, relative risk, or confidence interval. Therefore an eligible case-control comparison cannot be evaluated; no OR or 95% CI was computed because the required control counts are unavailable.

VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥2 **or** lower 95% CI ≥1.5).
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PS4 rule: case-control studies require p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).
  • Cavalieri et al. 2008, Table 2, mutation entry for exon 59: ATM c.8287C>T/p.Arg2763X was identified in patient AT43TO; the report provides no control comparison or case-control statistics.
  • Porcedda et al. 2008, Table 3 and Results: AT43TO carried c.8287C>T with c.5932G>T and was classified as A-T; the report provides diagnostic cohort data but no variant-specific unaffected-control comparison or PS4 statistics.
  • The literature_pass.json packet has an empty ai_classified_papers list; no already-read PS4 classifier paper was available to verify as case-control evidence.
Still missing
  • A case-control dataset with affected-carrier and matched unaffected or population-control counts, plus a p-value or sufficient data to calculate it, is unavailable.
Sources
cspec ↗PMID:17910737 ↗PMID:18431795 ↗
PM5 VCEPNot assessed: p.Arg2763Ter is upstream of p.Leu3048, but PM5 requires PVS1 Very Strong and that prerequisite was not established here. Details ▾Hide ▴
Reasoning

The ATM VCEP PM5 rule provides a DNA-variant route only for NMD-prone truncating variants receiving PVS1 at Very Strong with a premature termination codon upstream of p.Leu3048. This variant is a truncating nonsense change at p.Arg2763Ter and is upstream of p.Leu3048, but the requested group does not assess PVS1 and the available PVS1 variant-assessment file contains consequence facts only, not a VCEP-assigned PVS1 Very Strong result. Therefore the prerequisite cannot be established without evaluating PVS1 under the ATM PVS1 guide.

VCEP rule
* DNA Variants: Apply to all NMD-prone, truncating variants receiving PVS1 (must be at VeryStrong) with premature termination codons upstream of p.Leu3048
Evidence considered
  • The variant is a nonsense truncating change, p.Arg2763Ter, according to pvs1_variant_assessment.json.
  • The ATM VCEP PM5 rule requires: DNA variants must be NMD-prone truncating variants receiving PVS1 at Very Strong and have premature termination codons upstream of p.Leu3048.
  • The available PVS1 assessment records consequence_class=nonsense and p.Arg2763Ter but explicitly states that it contains variant facts only; it does not establish PVS1 strength.
Still missing
  • A VCEP-assigned PVS1 Very Strong result for this variant is required to evaluate the PM5 DNA route; pvs1_variant_assessment.json contains variant facts only and does not assign PVS1 strength.
Sources
cspec ↗pvs1_variant_assessment
PP1 VCEPNot assessed: the variant was reported in one affected proband, but no affected relative or familial segregation count is reported to meet the VCEP PP1 thresholds. Details ▾Hide ▴
Reasoning

PP1 is applicable only when affected relatives have both variants identified in the proband. The available literature identifies c.8287C>T as the second ATM allele in A-T patient AT43TO, and reports the patient as having A-T, but it does not report parental testing, additional affected relatives, or familial segregation. Therefore, the VCEP's one-, two-, or three-affected-relative PP1 thresholds cannot be evaluated.

VCEP rule
* AR Condition: Affected relatives must have both variants identified in proband. ... AR Condition: Segregation in ≥3 affected relatives ... AR Condition: Segregation in 2 affected relatives ... AR Condition: Segregation in 1 affected relative
Evidence considered
  • ATM VCEP v1.6 PP1 rule requires affected relatives to have both variants identified in the proband and assigns Supporting for segregation in 1 affected relative, Moderate for 2, and Strong for ≥3.
  • Cavalieri et al. 2008, Table 2, mutation entry for exon 59: patient AT43TO carried c.8287C>T as the second allele, written as p.Arg2763X; no familial segregation analysis was reported.
  • Porcedda et al. 2008, Table 3 and Results: AT43TO was classified as an A-T patient and carried c.5932G>T and c.8287C>T; no parental testing or affected-relative segregation was reported.
Still missing
  • Parental testing and phase are not reported.
  • No additional affected relatives with both ATM variants are reported.
  • No informative meioses or formal segregation analysis are reported.
Sources
cspec ↗PMID:17910737 ↗PMID:18431795 ↗
BS3 VCEPNot assessed: Table S1 directly measured c.8287C>T as Non-functional, while no variant-specific benign rescue result is available for BS3. Details ▾Hide ▴
Reasoning

No benign functional result is available for this variant. The exact Table S1 row reports Classification=Non-functional, Confidence=High, and DeepATM_predicted=No, which is direct evidence in the opposite direction and cannot support BS3. The approved ATM assay calibration file was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; it contains no variant-specific result, so the BS3 rescue requirements cannot be evaluated from that file.

VCEP rule
Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Evidence considered
  • Sun et al. 2025, Supplementary Table S1, row hg38 108343240 C>T / ATM c.8287C>T / R2763*: Classification=Non-functional; Confidence=High; DeepATM_predicted=No; this is not a benign functional result.
  • The VCEP's approved ATM assay calibration file was searched for c.8287C>T, p.Arg2763Ter, and p.R2763* and returned no variant-specific result; therefore its BS3 rescue thresholds cannot be applied to this variant.
Still missing
  • The file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched under c.8287C>T, p.Arg2763Ter, and p.R2763*; no variant-specific entry was found.
  • No approved ATM-specific assay result demonstrating rescue of an ATM feature or radiosensitivity was identified for this variant.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP2 VCEPNot assessed: no unaffected adult observation or cis observation is available for c.8287C>T under the ATM VCEP BP2 framework. Details ▾Hide ▴
Reasoning

BP2 requires an observation in an unaffected adult or an observation in cis with a pathogenic variant under the ATM VCEP's PM3/BP2 framework. The available evidence concerns an affected A-T proband, AT43TO, with two ATM variants and does not provide an unaffected adult observation or cis configuration for c.8287C>T. Therefore BP2 cannot be evaluated from the available evidence.

VCEP rule
BP2 Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. ... When assessing homozygous or in trans variants (with a likely pathogenic or pathogenic ATM variant) for possible downgrade in an unaffected individual, the individual should be 18 years or older with no evidence of A-T.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf states that BP2 concerns an unaffected non-A-T adult with a pathogenic or likely pathogenic variant in trans, or an observation in cis with a pathogenic variant; the available AT43TO evidence is an affected A-T case, not an unaffected adult.
  • Porcedda et al. 2008, PMID:18431795, Table 2 and Results: AT43TO was classified as an A-T patient, so this observation does not supply BP2 unaffected-adult evidence.
  • Cavalieri et al. 2008, PMID:17910737, Table 2: AT43TO is reported with two ATM alleles, but the report does not establish a cis configuration with a pathogenic variant or an unaffected adult status.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; no variant-specific entry was found.
  • No unaffected adult carrying c.8287C>T with a pathogenic or likely pathogenic ATM variant in trans, and no cis observation with a pathogenic variant, was identified in the available case evidence.
Sources
vcep_atm_pm3_bp2_1_6 ↗cspec ↗PMID:17910737 ↗PMID:18431795 ↗
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: c.8287C>T produces p.Arg2763Ter, whereas ATM PS1 covers missense changes or splice variants, not nonsense variants. Details ▾Hide ▴
Reasoning

The variant is a nonsense change, c.8287C>T (p.Arg2763Ter/p.R2763*), not a missense or splice variant. The ATM PS1 guide limits the missense route to missense changes and the alternate route to splicing variants; no matching entry for c.8287C>T, p.Arg2763Ter, or p.R2763* was found in ATM_PS1_1.6.pdf.

VCEP rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change • Missense: This rule may be applied only when a splice defect is ruled out for both alterations either by RNA analysis and/or in silico splice predictions • Splicing: Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. (PMID: 36865205)
Evidence considered
  • The case variant is NM_000051.4:c.8287C>T, encoding NP_000042.3:p.(Arg2763Ter)/p.(R2763*), with consequence_class=nonsense.
  • ATM_PS1_1.6.pdf was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; no matching variant entry was found.
  • The ATM VCEP PS1 rule states: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" and specifies the applicable routes as missense changes with splice defect ruled out or splicing variants evaluated with the ATM PS1 Splicing table.
Still missing
  • No entry for c.8287C>T, p.Arg2763Ter, or p.R2763* was found in ATM_PS1_1.6.pdf.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗pvs1_variant_assessment
PS2 VCEPNot applicable: the ATM VCEP prohibits PS2 because informative de novo occurrences have not yet been observed for AD or AR disease. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PS2 not applicable and explicitly states not to use it for autosomal dominant or autosomal recessive disease because informative de novo occurrences have not yet been observed and de novo autosomal recessive conditions are unlikely to be informed by phase.

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
  • ATM VCEP v1.6 PS2 criterion entry: applicability is Not applicable; instruction states not to use PS2 for AD or AR disease.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly instructs that PM1 is not to be used because benign and pathogenic variants are known within the same domains and germline mutational hotspots are not well defined. The authoritative vcep_materials.json domain_tables entry for ATM is absent, and no alternate PM1 route is provided by this VCEP.

VCEP rule
Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time
Evidence considered
  • The ATM VCEP PM1 instruction is: "Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time".
  • vcep_materials.json has domain_tables={}; therefore there is no authoritative ATM domain-table entry requiring residue 2763 to be checked against listed domains.
Sources
cspec ↗
PM4 N/ANot applicable: PM4 is limited to stop-loss variants, whereas c.8287C>T is a nonsense stop-gain producing p.Arg2763Ter. Details ▾Hide ▴
Reasoning

The ATM VCEP specifies PM4 for stop-loss variants. NM_000051.4:c.8287C>T is a nonsense stop-gain variant producing p.Arg2763Ter, not a stop-loss variant, so PM4 is outside the criterion's stated applicability.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • ATM VCEP CSPEC entry for PM4 states: Use for stop-loss variants.
  • Case variant assessment identifies c.8287C>T as a nonsense variant producing p.(Arg2763Ter), not stop-loss.
Sources
cspec ↗pvs1_variant_assessment
PM6 VCEPNot applicable: the ATM VCEP prohibits PM6 because informative de novo occurrences have not yet been observed for AD or AR disease. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PM6 not applicable and gives the same disease-level restriction as PS2: assumed de novo evidence is not used because informative de novo occurrences have not yet been observed and de novo autosomal recessive conditions are unlikely to be informed by phase.

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
  • ATM VCEP v1.6 PM6 criterion entry: applicability is Not applicable; instruction states not to use PM6 for AD or AR disease.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP says not to use PP2 because ATM lacks a defined low rate of benign missense variation. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly instructs not to use PP2 because ATM does not have a defined low rate of benign missense variation. The variant is also nonsense rather than missense, but the explicit VCEP prohibition is determinative.

VCEP rule
Do not use: ATM does not have a defined low rate of missense benign variation.
Evidence considered
  • The ATM VCEP PP2 instruction is: "Do not use: ATM does not have a defined low rate of missense benign variation."
Sources
cspec ↗
PP3 N/ANot applicable: PP3's VCEP splicing path covers silent, missense/in-frame, and specified intronic variants, not this nonsense variant; SpliceAI max delta was 0.149. Details ▾Hide ▴
Reasoning

The variant is a nonsense substitution, NM_000051.4:c.8287C>T (p.Arg2763Ter/p.R2763*). The ATM VCEP PP3 rule assigns its splicing path to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites, while its protein path is missense REVEL only. Therefore PP3 is not applicable to this nonsense variant, regardless of the available SpliceAI max delta score of 0.149. The governing Sun et al. 2025 Table S1 was searched under c.8287C>T, p.Arg2763Ter, and p.R2763*; the exact c.8287C>T row is present, but it is a nonsense row and does not pre-assign PP3.

VCEP rule
* Missense: REVEL **>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • ClinGen ATM VCEP v1.6 PP3 rule: the protein path is restricted to missense variants with REVEL >.7333, and the splicing path is restricted to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites with SpliceAI >=0.2.
  • SpliceAI result for NM_000051.4:c.8287C>T: DS_AG 0.026, DS_AL 0.149, DS_DG 0.000, DS_DL 0.098; max delta score 0.149.
  • Sun et al. 2025 Supplementary Table S1, exact row c.8287C>T / R2763* / exon_57 / Nonsense: CADD.phred 38, boostDM_score 0.97127473, REVEL NA, AlphaMissense NA, Classification Non-functional, Confidence High, DeepATM_predicted No. This row provides no pre-assigned PP3 code and is not used to convert a nonsense protein effect into PP3.
  • The governing ATM full-text directory was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; the exact c.8287C>T entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt, while the other two literal notations had no match.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP4 VCEPNot applicable: the ATM VCEP excludes PP4 for both hereditary breast cancer and ataxia telangiectasia interpretations. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP4 not applicable: it excludes PP4 for autosomal-dominant breast cancer because of genetic heterogeneity and excludes it as a separate line for autosomal-recessive ataxia telangiectasia because phenotype evidence is incorporated into the PM3/BP2 table.

VCEP rule
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. Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3|BP2 table
Evidence considered
  • ATM VCEP v1.6 PP4 applicability instruction: autosomal-dominant breast cancer PP4 is excluded because of genetic heterogeneity, and autosomal-recessive PP4 is not used separately because it is built into the Ataxia Telangiectasia PM3|BP2 table.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP prohibits PP5 regardless of the variant's pathogenic classifications in reputable sources. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP5 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; ClinVar or other reputable-source classifications therefore cannot establish PP5 here.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ATM VCEP v1.6 PP5 applicability instruction: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP v1.6 explicitly designates BS2 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 explicitly marks BS2 as Not Applicable; no BS2 evidence is evaluated.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC applicability entry for BS2: Not Applicable.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP assigns no weight to informative lack-of-segregation instances in ataxia-telangiectasia families because they are too rare. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS4 not applicable. It states that informative lack-of-co-segregation instances in ataxia-telangiectasia families are too rare to receive weight at this time; such observations may instead be considered for BP2 when biallelic unaffected patients are observed.

VCEP rule
AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.
Evidence considered
  • ATM VCEP v1.6 BS4 criterion entry: applicability is Not applicable; its AR instruction states that informative lack-of-co-segregation instances in A-T families are too rare to be considered for weight.
Sources
cspec ↗
BP1 VCEPNot applicable: BP1 is prohibited for ATM because missense pathogenic variants are known, and this variant is nonsense. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly instructs not to use BP1 because missense pathogenic variants are known for ATM. The variant is also nonsense rather than missense, so BP1 cannot apply to this variant type.

VCEP rule
Do not use: Missense pathogenic variants are known for ATM
Evidence considered
  • The ATM VCEP BP1 instruction is: "Do not use: Missense pathogenic variants are known for ATM".
  • The case variant has consequence_class=nonsense and encodes p.Arg2763Ter.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP explicitly designates BP3 as Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC marks BP3 as Not Applicable. The variant is a nonsense stop-gain rather than an in-frame deletion or insertion in a repetitive region, but the governing VCEP applicability designation independently excludes BP3.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC entry for BP3 states Not Applicable.
  • Case variant assessment identifies a nonsense stop-gain consequence, not an in-frame indel.
Sources
cspec ↗pvs1_variant_assessment
BP4 N/ANot applicable: BP4 cannot negate this nonsense variant's truncating effect; SpliceAI max delta 0.149 also exceeds the VCEP's <=0.1 no-impact cutoff. Details ▾Hide ▴
Reasoning

The variant is a nonsense substitution. Although the ATM VCEP BP4 rule includes a splicing path for no predicted SpliceAI impact, BP4 is not applicable to a nonsense variant because a no-splice-impact result does not negate the truncating protein effect. The available SpliceAI max delta score is 0.149, but it cannot establish BP4 for this variant type. The exact governing-table row was found in Sun et al. 2025 Supplementary Table S1 and does not pre-assign BP4.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • ClinGen ATM VCEP v1.6 BP4 rule: missense variants use REVEL <=.249; the splicing path is no predicted impact via splicing with SpliceAI <=0.1.
  • SpliceAI result for NM_000051.4:c.8287C>T: max delta score 0.149, with DS_AL 0.149 as the highest component score.
  • The exact Sun et al. 2025 Supplementary Table S1 row is c.8287C>T / R2763* / Nonsense, with Classification Non-functional, Confidence High, and DeepATM_predicted No; it does not pre-assign BP4.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP5 VCEPNot applicable: the ATM VCEP prohibits BP5 because additional pathogenic variants do not provide usable alternate-molecular-basis evidence in this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP5 not applicable and instructs not to use it because multiple pathogenic variants can occur without a noticeable phenotype difference and ATM's low penetrance increases the likelihood of additional pathogenic variants.

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
  • ATM VCEP v1.6 BP5 applicability instruction: do not use BP5 because cases with multiple pathogenic variants show no noticeable phenotype difference and ATM has low penetrance.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP prohibits BP6 regardless of any benign classification reported by a reputable source. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP6 not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; reputable-source benign classifications cannot establish BP6 here.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ATM VCEP v1.6 BP6 applicability instruction: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or qualifying deep intronic variants, whereas c.8287C>T is a nonsense substitution. Details ▾Hide ▴
Reasoning

The variant is a nonsense substitution, not a synonymous or deep intronic variant. The ATM VCEP BP7 rule is restricted to synonymous and deep intronic variants outside the specified donor and acceptor boundaries, with a separate RNA-observation path. No BP7 evidence can therefore be applied to NM_000051.4:c.8287C>T.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • ClinGen ATM VCEP v1.6 BP7 Supporting rule restricts BP7 to synonymous and deep intronic variants beyond the specified donor and acceptor boundaries; the variant consequence is nonsense.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.8287C>T
Protein (HGVS p.)
NP_000042.3:p.(Arg2763Ter)
GRCh38
chr11:108343240 C>T
GRCh37
chr11:108213967 C>T
Location and type
Exon 57 · nonsense
ClinVar
232612, 141233
COSMIC
COSV53734668

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 4 / 1,613,760 alleles AF 2.48e-06 · 0 homozygotes · FAF 7.9e-07
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 2.5e-06 · 4 / 1,613,760 alleles · 0 hom · FAF 7.9e-07
European (non-Finnish)4 / 1,179,898 3.4e-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.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.47868e-06; MAF= 0.00025%, 4/1613760 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39012e-06; MAF= 0.00034%, 4/1179898 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -18 bp
0.149
SpliceAI acceptor gainat +28 bp
0.026
SpliceAI donor lossat +131 bp
0.098
SpliceAI donor gainat -40 bp
0.000
Pangolin splice lossmagnitude shown
-0.309
Pangolin splice gain
0.032

Other predictors

REVEL
Not available
BayesDel
0.617

How the predictions were used

PP3 N/ANot applicable: PP3's VCEP splicing path covers silent, missense/in-frame, and specified intronic variants, not this nonsense variant; SpliceAI max delta was 0.149. Details ▾Hide ▴
Reasoning

The variant is a nonsense substitution, NM_000051.4:c.8287C>T (p.Arg2763Ter/p.R2763*). The ATM VCEP PP3 rule assigns its splicing path to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites, while its protein path is missense REVEL only. Therefore PP3 is not applicable to this nonsense variant, regardless of the available SpliceAI max delta score of 0.149. The governing Sun et al. 2025 Table S1 was searched under c.8287C>T, p.Arg2763Ter, and p.R2763*; the exact c.8287C>T row is present, but it is a nonsense row and does not pre-assign PP3.

VCEP rule
* Missense: REVEL **>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • ClinGen ATM VCEP v1.6 PP3 rule: the protein path is restricted to missense variants with REVEL >.7333, and the splicing path is restricted to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites with SpliceAI >=0.2.
  • SpliceAI result for NM_000051.4:c.8287C>T: DS_AG 0.026, DS_AL 0.149, DS_DG 0.000, DS_DL 0.098; max delta score 0.149.
  • Sun et al. 2025 Supplementary Table S1, exact row c.8287C>T / R2763* / exon_57 / Nonsense: CADD.phred 38, boostDM_score 0.97127473, REVEL NA, AlphaMissense NA, Classification Non-functional, Confidence High, DeepATM_predicted No. This row provides no pre-assigned PP3 code and is not used to convert a nonsense protein effect into PP3.
  • The governing ATM full-text directory was searched for c.8287C>T, p.Arg2763Ter, and p.R2763*; the exact c.8287C>T entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt, while the other two literal notations had no match.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP4 N/ANot applicable: BP4 cannot negate this nonsense variant's truncating effect; SpliceAI max delta 0.149 also exceeds the VCEP's <=0.1 no-impact cutoff. Details ▾Hide ▴
Reasoning

The variant is a nonsense substitution. Although the ATM VCEP BP4 rule includes a splicing path for no predicted SpliceAI impact, BP4 is not applicable to a nonsense variant because a no-splice-impact result does not negate the truncating protein effect. The available SpliceAI max delta score is 0.149, but it cannot establish BP4 for this variant type. The exact governing-table row was found in Sun et al. 2025 Supplementary Table S1 and does not pre-assign BP4.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • ClinGen ATM VCEP v1.6 BP4 rule: missense variants use REVEL <=.249; the splicing path is no predicted impact via splicing with SpliceAI <=0.1.
  • SpliceAI result for NM_000051.4:c.8287C>T: max delta score 0.149, with DS_AL 0.149 as the highest component score.
  • The exact Sun et al. 2025 Supplementary Table S1 row is c.8287C>T / R2763* / Nonsense, with Classification Non-functional, Confidence High, and DeepATM_predicted No; it does not pre-assign BP4.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or qualifying deep intronic variants, whereas c.8287C>T is a nonsense substitution. Details ▾Hide ▴
Reasoning

The variant is a nonsense substitution, not a synonymous or deep intronic variant. The ATM VCEP BP7 rule is restricted to synonymous and deep intronic variants outside the specified donor and acceptor boundaries, with a separate RNA-observation path. No BP7 evidence can therefore be applied to NM_000051.4:c.8287C>T.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • ClinGen ATM VCEP v1.6 BP7 Supporting rule restricts BP7 to synonymous and deep intronic variants beyond the specified donor and acceptor boundaries; the variant consequence is nonsense.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). BayesDel score = 0.61701.

10 paper records listed. 3 cited in the classification.

Cited in the classification

  • Large genomic mutations within the ATM gene detected by MLPA, including a duplication of 41 kb from exon 4 to 20.
    Cavalieri S et al. · 2008 Jan
    The paper explicitly reports ATM c.8287C>T, corresponding to p.Arg2763X, in patient AT43TO as the second allele and describes it as a nonsense mutation predicted to cause protein truncation. It provides variant-specific consequence evidence relevant to PVS1 but no variant-specific functional assay, segregation analysis, or population-frequency data.
    → PVS1 · very strong → PM3 · moderate Names this variant
    PMID 17910737 ↗
    Source detail
    59 AT43TOb AB c.8287C > T T(p.Arg2763X)

    Location Table 2, mutation entry for exon 59

    Context Multi-method mutation analysis of 21 Italian patients with ataxia-telangiectasia using STR/SNP haplotyping, DHPLC, and MLPA; the variant was identified by DHPLC-based point-mutation screening and sequencing.

  • A rapid flow cytometry test based on histone H2AX phosphorylation for the sensitive and specific diagnosis of ataxia telangiectasia.
    Porcedda P et al. · 2008 Jun
    The paper reports c.8287C>T in patient AT43TO together with c.5932G>T. AT43TO showed reduced ionizing-radiation-induced c-H2AX fluorescence in T-cell lines and PBMCs and was classified as an ataxia-telangiectasia patient. The paper does not provide the protein notation p.Arg2763Ter and does not isolate the contribution of c.8287C>T from the second allele.
    → PM3 · moderate Names this variant
    PMID 18431795 ↗
    Source detail
    AT43TO 7.30 n.a. c.5932G>T; c.8287C>T PBMCs ... AT43TO 9.10 n.a. c.5932G>T; c.8287C>T

    Location Table 3, 'Blind analysis of c-H2AX fluorescence after IR in patients referred for A-T differential diagnosis'; Results section, paragraph beginning 'Analysis of the means of c-H2AX after IR classified 15 patients as non-A-T and 4 as A-T'

    Context Patient AT43TO in a cohort of 19 consecutive patients suspected of ataxia-telangiectasia; ATM mutation testing by DHPLC and/or MLPA; functional assessment by flow-cytometric measurement of histone H2AX phosphorylation after 2 Gy ionizing radiation in T-cell lines and PBMCs.

  • Sun et al. 2025
    → PS3 · supporting
    PMID 40580951 ↗

Other 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 ↗
  • Recurrent R-spondin fusions in colon cancer.
    Seshagiri S et al. · 2012
    No paper-specific finding is recorded.
    PMID 22895193 ↗
  • Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.
    Huang Y et al. · 2013
    No paper-specific finding is recorded.
    PMID 23807571 ↗
  • 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 ↗
  • EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
    No paper-specific finding is recorded.
    PMID 20050888 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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

gnomAD v4.1 4 / 1,613,760 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.149 Open source ↗
ClinVar 8 Pathogenic · 1 pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 2.47868e-06; MAF= 0.00025%, 4/1613760 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.39012e-06; MAF= 0.00034%, 4/1179898 alleles, homozygotes = 0); grpmax FAF= 7.9e-07.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 232612)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). BayesDel score = 0.61701.

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 previously been reported in somatic cancers (COSMIC; COSV53734668, n = 6 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.