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ATMc.6814G>AUncertain significance
Print report
Variant interpretation report

ATM c.6814G>A, p.Glu2272Lys

NM_000051.4:c.6814G>A NP_000042.3:p.(Glu2272Lys) Missense · exon 47 View identifiers
Classification
Uncertain significance

Variant description:

The ATM NM_000051.4:c.6814G>A (NP_000042.3:p.(Glu2272Lys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV53744239, n = 7 times). Experimental evidence: Direct prime-editing data classify ATM c.6814G>A (E2272K) as Non-functional with Medium-high confidence and DeepATM_predicted=No. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PS3Supporting
PS3 · supporting

Met at Supporting: direct prime-editing data classify ATM c.6814G>A (E2272K) as Non-functional with Medium-high confidence and DeepATM_predicted=No.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met at Supporting: SpliceAI maximum delta 0.075 meets the VCEP no-predicted-impact threshold of ≤0.1, despite REVEL 0.686 not meeting ≤0.249.

Recorded classification: Uncertain significance

VUS: PS3 supporting and BP4 supporting are met, but neither criterion combination satisfies an ATM VCEP v1.6 pathogenic or benign rule.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
18 / 1,613,900 alleles

gnomAD v4.1: 18 / 1,613,900 alleles. Recorded AF 1.11531e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18532e-05; MAF= 0.00319%, 1/31394 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114811; MAF= 0.01148%, 1/8710 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.686 recorded score

Recorded REVEL score: 0.686. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
13 reported laboratory submissions

13 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

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

This variant has previously been reported in somatic cancers (COSMIC; COSV53744239, n = 7 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: 2 met · 6 not met · 4 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 this missense ATM variant, PS1 is not met because no different nucleotide change producing the same p.Glu2272Lys amino acid substitution was identified as an established pathogenic comparator.

PM1, PM5, PP2, and BP1 are not applicable under the ATM VCEP v1.6 rules.

The exact Sun et al. 2025 Table S1 row is a direct prime-editing measurement because DeepATM_predicted=No and Confidence=Medium-high.

Its Non-functional classification meets the VCEP file-specific PS3_Supporting mapping and is incompatible with BS3 rescue evidence.

The separate ClinGen ATM supplementary assay file was consulted and contains no exact entry for this variant, so it supplies calibration but no additional variant-specific result.

Within this requested group, PS4 is not assessed because the available variant-specific case-control report lacks the VCEP-required p-value, effect estimate, and lower 95% confidence interval; PP4, PP5, BP5, and BP6 are not applicable under the VCEP's explicit rules.

PP3 is not met because neither the VCEP missense REVEL threshold nor its SpliceAI splicing threshold is reached.

BP4 is met at Supporting strength through the VCEP's named SpliceAI no-predicted-impact path; BP4 and PP3 use distinct threshold directions and the same SpliceAI prediction is not counted as evidence for both criteria.

BP7 is not applicable because the variant is missense rather than synonymous or deep intronic.

Met · 2

PS3 SupportingVCEPMet at Supporting: direct prime-editing data classify ATM c.6814G>A (E2272K) as Non-functional with Medium-high confidence and DeepATM_predicted=No. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.6 limits PS3 Supporting to a variant that fails to rescue an ATM-specific feature, such as phosphorylation of ATM-specific targets, and excludes radiosensitivity-only evidence. Sun et al. 2025 Supplementary Table S1 contains the exact row for c.6814G>A / E2272K: Classification=Non-functional, Confidence=Medium-high, and DeepATM_predicted=No. Under the VCEP file-specific rule, DeepATM_predicted=No with Medium-high confidence makes this a direct prime-editing measurement, and Non-functional maps to PS3_Supporting. The approved-assay calibration file was searched for c.6814G>A, p.Glu2272Lys, and p.E2272K; it contains methodology and calibration only, with no exact variant entry, so no conflicting approved-assay direction was identified.

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 c.6814G>A / E2272K: Classification=Non-functional; Confidence=Medium-high; DeepATM_predicted=No; Combined_score=-4.06655320417108.
  • The VCEP's file-specific PS3/BS3 rule states that DeepATM_predicted=No with High, Medium-high, or Medium confidence is a direct prime-editing measurement, and Classification=Non-functional maps to PS3_Supporting.
  • ClinGen HBOP ATM VCEP v1.6 PS3 Supporting rule: use when a variant fails to rescue an ATM-specific feature, such as phosphorylation of ATM-specific targets; radiosensitivity-only evidence is excluded.
  • The approved ATM functional-assay calibration file was searched under c.6814G>A, p.Glu2272Lys, and p.E2272K and returned no exact variant entry; its rows describe approved assay methodology, controls, thresholds, and proposed strengths rather than current-variant results.
Still missing
  • The ClinGen HBOP ATM supplementary assay-calibration file has no exact entry for c.6814G>A, p.Glu2272Lys, or p.E2272K; it is a methodology/calibration table rather than a per-variant results table.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
BP4 SupportingVCEPMet at Supporting: SpliceAI maximum delta 0.075 meets the VCEP no-predicted-impact threshold of ≤0.1, despite REVEL 0.686 not meeting ≤0.249. Details ▾Hide ▴
Reasoning

The variant is a missense substitution. Under the VCEP BP4 rule, the missense path is not met because REVEL is 0.686, above the ≤0.249 cutoff; the VCEP also explicitly provides a splicing path, and SpliceAI maximum delta score is 0.075, meeting the no-predicted-impact threshold of ≤0.1. Applying that named splicing path, BP4 is met at Supporting strength. The governing Table S1 row for c.6814G>A reports REVEL 0.686 and Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; it is corroborative only and does not replace the VCEP BP4 rule.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • REVEL lookup for NM_000051.4:c.6814G>A / NP_000042.3:p.(E2272K): score 0.686, which is above the VCEP BP4 missense cutoff of ≤0.249.
  • SpliceAI Lookup for NM_000051.4:c.6814G>A: DS_AG=0.019, DS_AL=0.075, DS_DG=0.000, DS_DL=0.016; maximum delta score=0.075, which is ≤0.1.
  • Sun et al. 2025, Supplementary Table S1, row ATM c.6814G>A (E2272K): REVEL=0.686, Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; used only as corroboration and not as the source of BP4.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Not met · 6 · evaluated, threshold not reached

PS1 VCEPNot met: no previously established pathogenic ATM variant with the same p.Glu2272Lys amino acid change was identified, and the governing PS1 guide has no matching entry. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PS1 for a missense change only when a splice defect is ruled out for both the assessed variant and the previously established pathogenic variant, and the underlying PS1 definition requires the same amino acid change as that pathogenic variant. The governing ATM PS1 guide was searched for c.6814G>A, p.Glu2272Lys, and p.E2272K; no entry was found. PMID:12673804 reports the assessed E2272K variant itself, not a different nucleotide change producing the same amino acid substitution, and no other established pathogenic p.Glu2272Lys/p.E2272K comparator was identified. Therefore PS1 is not met.

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
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PS1 rule: missense PS1 may be used only when splicing is ruled out for both alterations.
  • ATM_PS1_1.6.pdf.txt was searched under c.6814G>A, p.Glu2272Lys, and p.E2272K; no matching variant entry was present.
  • PMID:12673804, Results/Table 2: E2272K was reported as a germline alteration in patient B-A2, but this is the assessed variant itself rather than a different nucleotide change causing the same amino acid change.
Still missing
  • ATM_PS1_1.6.pdf.txt was searched for c.6814G>A, p.Glu2272Lys, and p.E2272K; no entry for this variant was found.
  • No different nucleotide change producing the same p.Glu2272Lys/p.E2272K amino acid substitution was identified as an established pathogenic comparator.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗PMID:12673804 ↗
PM2 VCEPNot met: gnomAD v4.1 highest-subpopulation AF is 0.00267%, above the VCEP's <=0.001% PM2 threshold, with 2 African alleles. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PM2 at Supporting strength when frequency is <=0.001% in the gnomAD subpopulation with the highest frequency, with an exception for >0.001% when n=1 in a single subpopulation and the variant is absent from all others. Using the default all-comers gnomAD sources because the VCEP rule does not specify a non-cancer or exome-only source, gnomAD v4.1 shows the highest subpopulation AF as 2.67023e-05 (0.00267%) with 2 alleles and 18 total alleles, so the n=1 exception does not apply; gnomAD v2.1 also shows 1 allele in the African/African American subgroup and the variant is present in the combined dataset. PM2 is not 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 HBOP ATM VCEP Version 1.6 CSPEC PM2 rule: Frequency <=.001% in gnomAD subpopulation with the highest frequency; exception when >.001% but n=1 in a single subpopulation not present in any other subpopulation.
  • gnomAD v4.1 all-comers: highest observed subpopulation African/African American AF=2.67022696929239e-05 (0.00267%), AC=2, AN=74900; total AC=18, AN=1613900; homozygotes=0.
  • gnomAD v2.1 all-comers: highest observed subpopulation African/African American AF=0.0001148105625717566 (0.01148%), AC=1, AN=8710; total AC=1, AN=31394; homozygotes=0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
PP3 VCEPNot met: REVEL 0.686 is below >0.7333 and SpliceAI maximum delta 0.075 is below the ≥0.2 PP3 threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the VCEP PP3 missense and permitted splicing paths were evaluated. REVEL is 0.686, below the VCEP missense threshold of >0.7333. SpliceAI maximum delta score is 0.075, below the VCEP splicing threshold of ≥0.2 for missense variants. The governing VCEP rule therefore supplies no PP3 evidence. The governing Table S1 row for c.6814G>A reports REVEL 0.686 and Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; these table predictors are corroborative only and do not change the PP3 result.

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
  • REVEL lookup for NM_000051.4:c.6814G>A / NP_000042.3:p.(E2272K): score 0.686.
  • SpliceAI Lookup for NM_000051.4:c.6814G>A: DS_AG=0.019, DS_AL=0.075, DS_DG=0.000, DS_DL=0.016; maximum delta score=0.075.
  • Sun et al. 2025, Supplementary Table S1, row ATM c.6814G>A (E2272K): REVEL=0.686, Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; used only as corroboration because the VCEP rule names REVEL and SpliceAI for PP3.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax FAF is 8.03e-06 (0.000803%), below the VCEP's >0.5% BA1 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies BA1 when the gnomAD group maximum filtering allele frequency exceeds 0.5%. The available all-comers gnomAD v4.1 record has grpmax FAF 8.03e-06 (0.000803%), and the highest observed subpopulation AF is 2.67023e-05 (0.00267%), both below 0.5%; gnomAD v2.1 likewise has a highest observed subpopulation AF of 0.000114811 (0.01148%). Therefore BA1 is not met.

VCEP rule
Grpmax Filtering AF >.5% in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP Version 1.6 CSPEC BA1 rule: Grpmax Filtering AF >.5% in gnomAD.
  • gnomAD v4.1 all-comers: grpmax FAF=8.03e-06; highest observed subpopulation was African/African American AF=2.67022696929239e-05 (2/74900 alleles), homozygotes=0.
  • gnomAD v2.1 all-comers: highest observed subpopulation was African/African American AF=0.0001148105625717566 (1/8710 alleles), homozygotes=0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax FAF is 8.03e-06 (0.000803%), below the VCEP's >0.05% BS1 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies BS1 when the gnomAD group maximum filtering allele frequency exceeds 0.05%. The available all-comers gnomAD v4.1 record has grpmax FAF 8.03e-06 (0.000803%), and its highest observed subpopulation AF is 2.67023e-05 (0.00267%), both below 0.05%; gnomAD v2.1 also remains below the threshold. Therefore BS1 is not met.

VCEP rule
Grpmax Filtering AF >.05% in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP Version 1.6 CSPEC BS1 rule: Grpmax Filtering AF >.05% in gnomAD.
  • gnomAD v4.1 all-comers: grpmax FAF=8.03e-06; highest observed subpopulation AF=2.67022696929239e-05 (2/74900 alleles), homozygotes=0.
  • gnomAD v2.1 all-comers: highest observed subpopulation AF=0.0001148105625717566 (1/8710 alleles), homozygotes=0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS3 VCEPNot met: direct prime-editing data classify ATM c.6814G>A (E2272K) as Non-functional, providing no evidence that the variant rescues ATM function for BS3. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.6 defines BS3 Supporting for a variant that rescues either an ATM-specific feature or radiosensitivity, and BS3 Moderate for rescue of both. The exact Sun et al. 2025 Supplementary Table S1 row for c.6814G>A / E2272K reports Classification=Non-functional, Confidence=Medium-high, and DeepATM_predicted=No, which is direct prime-editing evidence of loss rather than preserved function. Therefore the result does not support BS3 and directly opposes a benign functional interpretation. The approved-assay calibration file was searched for c.6814G>A, p.Glu2272Lys, and p.E2272K and contains no exact variant result.

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 c.6814G>A / E2272K: Classification=Non-functional; Confidence=Medium-high; DeepATM_predicted=No; Combined_score=-4.06655320417108.
  • The VCEP's file-specific PS3/BS3 rule states that DeepATM_predicted=No with High, Medium-high, or Medium confidence is a direct prime-editing measurement, and Classification=Functional maps to BS3_Supporting; this row is Non-functional instead.
  • ClinGen HBOP ATM VCEP v1.6 BS3 Supporting rule: use when a variant rescues either an ATM-specific feature or rescues radiosensitivity.
  • The approved ATM functional-assay calibration file was searched under c.6814G>A, p.Glu2272Lys, and p.E2272K and returned no exact variant entry; no approved-assay result provides a conflicting benign direction.
Still missing
  • The ClinGen HBOP ATM supplementary assay-calibration file has no exact entry for c.6814G>A, p.Glu2272Lys, or p.E2272K; it is a methodology/calibration table rather than a per-variant results table.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗

Not assessed · 4 · no assessment recorded

PS4 VCEPNot assessed: one variant allele in 114 ALL cases versus zero in 138 controls is reported, but the required p-value, effect estimate, and lower 95% confidence interval are unavailable. Details ▾Hide ▴
Reasoning

The VCEP's applicable PS4 rule requires case-control studies with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥2 or a lower 95% confidence interval ≥1.5. PMID:12673804 reports ATM c.6814G>A (p.E2272K) in 1 of 114 childhood ALL patient alleles and 0 of 138 control alleles, but the source does not provide the required p-value, effect estimate, or lower 95% confidence interval. The available report therefore does not permit evaluation of the VCEP's complete PS4 rule; no case-control PS4 assertion is made.

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
  • Gumy Pause et al. 2003, PMID:12673804, Results/Table 2: ATM c.6814G>A (p.E2272K) was found as a germline alteration in 1 of 114 childhood ALL patient alleles and 0 of 138 control alleles; no p-value, odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is provided.
  • The VCEP PS4 rule requires p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).
Still missing
  • A case-control p-value is not reported.
  • An odds ratio, hazard ratio, or relative risk is not reported.
  • The lower 95% confidence interval is not reported.
Sources
cspec ↗PMID:12673804 ↗
PM3 VCEPNot assessed: the reported germline observation lacks an A-T proband, a pathogenic ATM variant in trans, and phase information required for PM3 points. Details ▾Hide ▴
Reasoning

The ATM VCEP PM3 rule requires the variant to be detected in trans with a pathogenic variant in an A-T proband, with points determined by phenotype confidence and phase. PMID:12673804 reports germline c.6814G>A (p.E2272K) in a child with B-precursor acute lymphoblastic leukemia, but provides no A-T diagnosis or qualifying A-T phenotype, no second pathogenic ATM variant, and no phase information. The governing ATM_PM3_BP2_1.6.pdf table contains no row for c.6814G>A, p.Glu2272Lys, or p.E2272K. Therefore, the available evidence cannot be assigned PM3 points.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant ... Co-occurrent P or LP variant should be assigned classification using VCEP specifications. Stipulation for in trans can be met by genotyping of at least one parent or assumed if VUA is seen with at least 2 different P/LP variants.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf: PM3 is for a recessive disorder when the variant is detected in trans with a pathogenic variant; its A-T table assigns points per unrelated A-T proband according to phenotype confidence and phase.
  • ATM_PM3_BP2_1.6.pdf: the searched converted full text has no matching entry for c.6814G>A, p.Glu2272Lys, or p.E2272K.
  • Gumy Pause et al. 2003, PMID:12673804, Results/Table 2: ATM c.6814G>A (p.E2272K) was a germline alteration in patient B-A2 with childhood B-precursor acute lymphoblastic leukemia; it was observed in 1 of 114 patient alleles and 0 of 138 control alleles, with no loss of heterozygosity at the ATM locus. The report does not establish A-T, a second pathogenic ATM allele, or phase.
Still missing
  • No entry for c.6814G>A, p.Glu2272Lys, or p.E2272K was found in ATM_PM3_BP2_1.6.pdf.txt.
  • A qualifying A-T phenotype and laboratory findings are not available for the reported patient.
  • A second pathogenic or likely pathogenic ATM variant and confirmed phase are not available.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗PMID:12673804 ↗
PP1 VCEPNot assessed: the report describes one affected patient but provides no affected-relative segregation count, parental testing, or meiosis data for the PP1 threshold. Details ▾Hide ▴
Reasoning

PP1 is applicable only on the VCEP's AR segregation path, with strength determined by the number of affected relatives. The available exact-variant report describes one patient with germline ATM c.6814G>A (p.E2272K) but provides no affected-relative segregation data, parental testing, or meioses; therefore no PP1 strength can be assigned.

VCEP rule
AR Condition: Segregation in 1 affected relative; AR Condition: Segregation in 2 affected relatives; AR Condition: Segregation in ≥3 affected relatives
Evidence considered
  • ATM VCEP v1.6 PP1 rules provide supporting strength for segregation in 1 affected relative, moderate strength for 2 affected relatives, and strong strength for at least 3 affected relatives; the VCEP also says the AD condition is not to be used.
  • Gumy Pause et al. 2003, Results section 'ATM alterations of probable biological significance' and Table 2: ATM c.6814G>A (p.E2272K) was reported as a germline alteration in patient B-A2 with childhood B-precursor ALL; the report does not provide affected-relative segregation, parental testing, or meiosis data.
Still missing
  • Affected-relative segregation data and the number of informative affected relatives are unavailable.
  • Parental testing and phase information are unavailable.
Sources
cspec ↗PMID:12673804 ↗
BP2 VCEPNot assessed: no unaffected adult observation, pathogenic ATM co-allele, or cis/trans phase is documented for the reported germline variant. Details ▾Hide ▴
Reasoning

The ATM VCEP BP2 rule requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant, and its BP2 table assigns negative points per unaffected non-A-T adult proband. PMID:12673804 reports germline p.E2272K in a child with acute lymphoblastic leukemia, not an unaffected non-A-T adult, and reports neither a pathogenic variant in cis or trans nor phase. The governing ATM_PM3_BP2_1.6.pdf table contains no row for c.6814G>A, p.Glu2272Lys, or p.E2272K. Therefore, BP2 cannot be evaluated from the available evidence.

VCEP rule
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: BP2 is 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; the BP2 table concerns unaffected non-A-T adults and assigns -1, -2, or <=-4 points by phase and setting.
  • ATM_PM3_BP2_1.6.pdf: the searched converted full text has no matching entry for c.6814G>A, p.Glu2272Lys, or p.E2272K.
  • Gumy Pause et al. 2003, PMID:12673804, Results/Table 2: p.E2272K was reported as a germline alteration in a child with childhood B-precursor acute lymphoblastic leukemia; the report does not document an unaffected adult, a pathogenic ATM co-allele, or cis/trans phase.
Still missing
  • No entry for c.6814G>A, p.Glu2272Lys, or p.E2272K was found in ATM_PM3_BP2_1.6.pdf.txt.
  • An unaffected non-A-T adult observation is not available.
  • A pathogenic or likely pathogenic co-occurring variant and confirmed cis/trans phase are not available.
Sources
cspec ↗vcep_atm_pm3_bp2_1_6 ↗PMID:12673804 ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.6814G>A is a missense substitution, whereas the ATM VCEP PVS1 rule is limited to null variants. Details ▾Hide ▴
Reasoning

The variant is NM_000051.4:c.6814G>A, an exon 47 missense substitution encoding p.(Glu2272Lys), not a nonsense, frameshift, canonical splice, initiation-codon, or exon-deletion loss-of-function allele. The ATM VCEP PVS1 rule is restricted to null variants; therefore NMD prediction, exon importance, and protein truncation considerations do not create a PVS1 path for this missense variant. The governing ATM_PVS1_1.6.pdf file was searched for c.6814G>A, p.Glu2272Lys, and p.E2272K; no variant-specific entry was found, consistently with the variant being outside the listed PVS1 variant classes.

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
Evidence considered
  • Case normalization: NM_000051.4:c.6814G>A; NP_000042.3:p.(Glu2272Lys); exon 47; consequence class missense.
  • ATM_PVS1_1.6.pdf, PVS1 definition: the listed eligible classes are nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, and single or multi-exon deletion.
  • ATM_PVS1_1.6.pdf was searched under c.6814G>A, p.Glu2272Lys, and p.E2272K; no matching variant-specific row or assignment was found.
Still missing
  • ATM_PVS1_1.6.pdf was searched for c.6814G>A, p.Glu2272Lys, and p.E2272K; no variant-specific entry was found.
Sources
cspec ↗
PS2 VCEPNot applicable: the ATM VCEP prohibits PS2 for AD or AR disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PS2 not applicable and instructs that de novo evidence is not used for either autosomal dominant or autosomal recessive disease because informative de novo occurrences have not been observed and de novo 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 CSPEC criterion entry for PS2: applicability is Not Applicable; its use instruction excludes PS2 for AD and 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 marks PM1 as not applicable and instructs curators not to use it because benign and pathogenic variants are known within the same domains and germline mutational hotspots are not well defined. The case vcep_materials.json domain_tables object is empty, so there is no gene-specific authoritative domain-table entry that overrides this VCEP applicability rule.

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
  • ATM VCEP v1.6 PM1 instructions: PM1 is not applicable because benign and pathogenic variants are known within the same domains and germline mutational hotspots are not well defined.
  • vcep_materials.json domain_tables: {} for ATM; no authoritative gene-specific domain-table entry was available.
Sources
cspec ↗
PM4 N/ANot applicable: p.(Glu2272Lys) is a missense substitution with no protein-length change, while the VCEP PM4 rule applies to stop-loss variants. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, p.(Glu2272Lys), with no protein-length change or stop-loss consequence. The ATM VCEP PM4 rule applies specifically to stop-loss variants, so PM4 is not applicable.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • Case normalization identifies p.(Glu2272Lys) and consequence class missense, with no stop-loss or protein-length-change consequence.
  • ATM VCEP CSPEC PM4 entry specifies the criterion for stop-loss variants.
Sources
cspec ↗
PM5 N/ANot applicable: ATM VCEP PM5 excludes missense changes, including this p.Glu2272Lys variant, despite same-residue missense entries in Table S1. Details ▾Hide ▴
Reasoning

The ATM VCEP's PM5 instruction specifically excludes missense changes because multiple amino acid substitutions at the same residue can be pathogenic or benign and bioinformatic tools cannot yet confidently distinguish them. The assessed variant is missense, c.6814G>A (p.Glu2272Lys), so same-residue missense observations in Sun et al. 2025 Supplementary Table S1 do not activate PM5 under this VCEP.

VCEP rule
Do not use for missense changes: Multiple amino acid substitutions at the same residue can be pathogenic or benign and bioinformatic tools cannot yet confidently distinguish them
Evidence considered
  • ATM VCEP v1.6 PM5 instruction: do not use PM5 for missense changes because substitutions at the same residue can be pathogenic or benign.
  • Sun et al. 2025, Supplementary Table S1, rows ATM c.6814G>C p.E2272Q; c.6815A>T p.E2272V; c.6815A>G p.E2272G; c.6815A>C p.E2272A; and c.6816A>C p.E2272D: same-residue missense observations were present, but the VCEP PM5 rule excludes this evidence type.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PM6 VCEPNot applicable: the ATM VCEP prohibits PM6 for AD or AR disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PM6 not applicable and instructs that de novo evidence is not used for either autosomal dominant or autosomal recessive disease because informative de novo occurrences have not been observed and de novo 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 CSPEC criterion entry for PM6: applicability is Not Applicable; its use instruction excludes PM6 for AD and AR disease.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP states that ATM does not have a defined low rate of benign missense variation. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP2 as not applicable and states that ATM does not have a defined low rate of missense benign variation. Therefore PP2 cannot be applied to this missense variant under the governing VCEP specification.

VCEP rule
Do not use: ATM does not have a defined low rate of missense benign variation.
Evidence considered
  • ATM VCEP v1.6 PP2 instructions: do not use because ATM does not have a defined low rate of missense benign variation.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP prohibits PP4 for ATM-related breast cancer and incorporates ataxia-telangiectasia phenotype evidence into the PM3|BP2 table. Details ▾Hide ▴
Reasoning

The VCEP marks PP4 not applicable. It specifically instructs that PP4 must not be used for autosomal-dominant breast cancer because of genetic heterogeneity and lack of features distinguishing hereditary from sporadic disease, and must not be used as a separate line of evidence for autosomal-recessive ataxia-telangiectasia because that evidence is built 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
  • ClinGen HBOP ATM VCEP v1.6 PP4 entry: PP4 is marked Not applicable; the instructions prohibit use for autosomal-dominant breast cancer and prohibit separate use for autosomal-recessive ataxia-telangiectasia.
Sources
cspec ↗
PP5 VCEPNot applicable: the VCEP explicitly prohibits PP5, so the variant's ClinVar submissions cannot establish this criterion. Details ▾Hide ▴
Reasoning

The 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. The available ClinVar record is therefore not used as PP5 evidence.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PP5 entry: PP5 is marked Not Applicable for this VCEP and is not for use.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP Version 1.6 explicitly marks BS2 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP Version 1.6 marks BS2 as Not Applicable. No BS2 assessment is made.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP Version 1.6 CSPEC entry for BS2: applicability is Not Applicable.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP gives no BS4 weight because informative lack-of-co-segregation in A-T families is too rare. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS4 not applicable. For ATM, informative lack-of-co-segregation in ataxia-telangiectasia families is considered too rare to receive weight, and the VCEP separately notes that such observations may be considered for BP2 when biallelic unaffected patients are observed in an ataxia-telangiectasia family.

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 CSPEC criterion entry for BS4: applicability is Not Applicable; its AR instruction excludes weight for informative lack-of-co-segregation in A-T families.
Sources
cspec ↗
BP1 VCEPNot applicable: BP1 is prohibited for ATM because missense pathogenic variants are known in this gene. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP1 as not applicable because missense pathogenic variants are known for ATM. This missense variant therefore cannot receive BP1 under the governing VCEP specification.

VCEP rule
Do not use: Missense pathogenic variants are known for ATM
Evidence considered
  • ATM VCEP v1.6 BP1 instructions: do not use because missense pathogenic variants are known for ATM.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP explicitly designates BP3 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC entry explicitly marks BP3 as Not Applicable. The variant is also a missense substitution rather than an in-frame deletion or insertion in a repetitive region, but no generic BP3 rule is substituted for the VCEP designation.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC BP3 entry: applicability is Not Applicable.
  • Case normalization identifies p.(Glu2272Lys) as a missense substitution, not an in-frame deletion or insertion.
Sources
cspec ↗
BP5 VCEPNot applicable: the VCEP prohibits BP5 because multiple pathogenic variants may coexist without phenotype differences and ATM has low penetrance. Details ▾Hide ▴
Reasoning

The VCEP marks BP5 not applicable and instructs not to use it because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference, while ATM's low penetrance makes co-occurrence with other pathogenic variants more frequent in the general population.

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
  • ClinGen HBOP ATM VCEP v1.6 BP5 entry: BP5 is marked Not applicable and its instructions say Do not use for the stated phenotype and penetrance reasons.
Sources
cspec ↗
BP6 VCEPNot applicable: the VCEP explicitly prohibits BP6, so the variant's ClinVar classification cannot establish this criterion. Details ▾Hide ▴
Reasoning

The 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. The available ClinVar classification is therefore not used as BP6 evidence.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 BP6 entry: BP6 is marked Not Applicable for this VCEP and is not for use.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is limited to synonymous or deep intronic variants, whereas this variant is missense. Details ▾Hide ▴
Reasoning

The variant is missense, whereas the VCEP BP7 rule applies to synonymous and deep intronic variants outside the specified donor and acceptor regions, or to observed RNA evidence for silent and intronic variants. Therefore BP7 is outside its governing scope and is not applicable.

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
  • Case variant consequence: NM_000051.4:c.6814G>A is a missense variant encoding NP_000042.3:p.(Glu2272Lys) / p.(E2272K).
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.6814G>A
Protein (HGVS p.)
NP_000042.3:p.(Glu2272Lys)
GRCh38
chr11:108326064 G>A
GRCh37
chr11:108196791 G>A
Location and type
Exon 47 · missense
ClinVar
265315
COSMIC
COSV53744239

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 18 / 1,613,900 alleles AF 1.12e-05 · 0 homozygotes · FAF 8.03e-06
gnomAD v2.1 1 / 31,394 alleles AF 3.19e-05 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.1e-05 · 18 / 1,613,900 alleles · 0 hom · FAF 8e-06
African/African American2 / 74,900 2.7e-05
European (non-Finnish)16 / 1,179,978 1.4e-05
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 3.2e-05 · 1 / 31,394 alleles · 0 hom
African/African American1 / 8,710 0.00011
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.11531e-05; MAF= 0.00112%, 18/1613900 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67023e-05; MAF= 0.00267%, 2/74900 alleles, homozygotes = 0); grpmax FAF= 8.03e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18532e-05; MAF= 0.00319%, 1/31394 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114811; MAF= 0.01148%, 1/8710 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -6 bp
0.075
SpliceAI acceptor gainat +27 bp
0.019
SpliceAI donor lossat +161 bp
0.016
SpliceAI donor gainat -6 bp
0.000
Pangolin splice lossmagnitude shown
-0.095
Pangolin splice gain
0.020

Other predictors

REVEL
0.686
BayesDel
0.328

How the predictions were used

BP4 SupportingVCEPMet at Supporting: SpliceAI maximum delta 0.075 meets the VCEP no-predicted-impact threshold of ≤0.1, despite REVEL 0.686 not meeting ≤0.249. Details ▾Hide ▴
Reasoning

The variant is a missense substitution. Under the VCEP BP4 rule, the missense path is not met because REVEL is 0.686, above the ≤0.249 cutoff; the VCEP also explicitly provides a splicing path, and SpliceAI maximum delta score is 0.075, meeting the no-predicted-impact threshold of ≤0.1. Applying that named splicing path, BP4 is met at Supporting strength. The governing Table S1 row for c.6814G>A reports REVEL 0.686 and Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; it is corroborative only and does not replace the VCEP BP4 rule.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • REVEL lookup for NM_000051.4:c.6814G>A / NP_000042.3:p.(E2272K): score 0.686, which is above the VCEP BP4 missense cutoff of ≤0.249.
  • SpliceAI Lookup for NM_000051.4:c.6814G>A: DS_AG=0.019, DS_AL=0.075, DS_DG=0.000, DS_DL=0.016; maximum delta score=0.075, which is ≤0.1.
  • Sun et al. 2025, Supplementary Table S1, row ATM c.6814G>A (E2272K): REVEL=0.686, Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; used only as corroboration and not as the source of BP4.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP3 VCEPNot met: REVEL 0.686 is below >0.7333 and SpliceAI maximum delta 0.075 is below the ≥0.2 PP3 threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the VCEP PP3 missense and permitted splicing paths were evaluated. REVEL is 0.686, below the VCEP missense threshold of >0.7333. SpliceAI maximum delta score is 0.075, below the VCEP splicing threshold of ≥0.2 for missense variants. The governing VCEP rule therefore supplies no PP3 evidence. The governing Table S1 row for c.6814G>A reports REVEL 0.686 and Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; these table predictors are corroborative only and do not change the PP3 result.

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
  • REVEL lookup for NM_000051.4:c.6814G>A / NP_000042.3:p.(E2272K): score 0.686.
  • SpliceAI Lookup for NM_000051.4:c.6814G>A: DS_AG=0.019, DS_AL=0.075, DS_DG=0.000, DS_DL=0.016; maximum delta score=0.075.
  • Sun et al. 2025, Supplementary Table S1, row ATM c.6814G>A (E2272K): REVEL=0.686, Classification=Non-functional, Confidence=Medium-high, DeepATM_predicted=No; used only as corroboration because the VCEP rule names REVEL and SpliceAI for PP3.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 N/ANot applicable: BP7 is limited to synonymous or deep intronic variants, whereas this variant is missense. Details ▾Hide ▴
Reasoning

The variant is missense, whereas the VCEP BP7 rule applies to synonymous and deep intronic variants outside the specified donor and acceptor regions, or to observed RNA evidence for silent and intronic variants. Therefore BP7 is outside its governing scope and is not applicable.

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
  • Case variant consequence: NM_000051.4:c.6814G>A is a missense variant encoding NP_000042.3:p.(Glu2272Lys) / p.(E2272K).
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.686. BayesDel score = 0.328155.

8 paper records listed. 1 cited in the classification.

Cited in the classification

  • Sun et al. 2025
    Sun et al. Supplementary Table S1 contains the assessed ATM c.6814G>A p.E2272K row and multiple other missense substitutions at residue E2272, including p.E2272Q, p.E2272V, p.E2272G, p.E2272A, and p.E2272D.
    → PS3 · supporting Names this variant
    PMID 40580951 ↗
    Source detail
    108326064 G C c.6814G>C E2272Q exon_47 11 Missense 108326064 G A c.6814G>A E2272K exon_47 11 Missense

    Location Supplementary Table S1 converted full text, residue 2272 rows

    Context Systematic ATM SNV functional assessment reported in Supplementary Table S1; the table includes variant consequence, computational scores, functional classification, and confidence fields.

Other recorded publications

  • 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 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Functional classification of ATM variants in ataxia-telangiectasia patients.
    Fiévet A et al. · 2019
    No paper-specific finding is recorded.
    PMID 31050087 ↗
  • Reclassification of ATM Missense Variants of Uncertain Significance by Integrating Results from Systematic Functional Assays into an ACMG Points-Based Framework.
    Hanenberg H et al. · 2025
    No paper-specific finding is recorded.
    PMID 40105422 ↗
  • ATM gene alterations in childhood acute lymphoblastic leukemias.
    Gumy Pause F et al. · 2003
    The paper identified ATM c.6814G>A (p.E2272K) in patient B-A2 with childhood B-precursor acute lymphoblastic leukemia. The variant was a germline alteration, was classified by the authors as probably biologically significant, and was described as a non-conservative acidic-to-basic substitution in the conserved Rad-3 domain. It was observed in 1 of 114 patient alleles and 0 of 138 control alleles. Comparison with remission blood samples showed no loss of heterozygosity at the ATM locus.
    Names this variant
    PMID 12673804 ↗
    Quoted passage
    E2272K, found as a germline alteration in B-A2, induces a significant biological change (acidic? basic) in the Rad-3 domain.

    Results, ATM alterations of probable biological significance; Table 2

  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    No paper-specific finding is recorded.
    PMID 17508274 ↗
  • The emerging landscape of breast cancer susceptibility.
    No paper-specific finding is recorded.
    PMID 18163131 ↗
  • Ataxia-Telangiectasia.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301790 ↗

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

gnomAD v4.1 18 / 1,613,900 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.075 Open source ↗
ClinVar 13 Uncertain significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.11531e-05; MAF= 0.00112%, 18/1613900 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67023e-05; MAF= 0.00267%, 2/74900 alleles, homozygotes = 0); grpmax FAF= 8.03e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18532e-05; MAF= 0.00319%, 1/31394 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114811; MAF= 0.01148%, 1/8710 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (13 clinical laboratories). (ClinVarID = 265315)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.686. BayesDel score = 0.328155.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53744239, n = 7 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.