The ATM NM_000051.4:c.6095G>A (NP_000042.3:p.(Arg2032Lys)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Direct prime editing classified ATM c.6095G>A 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.
This variantScenario
BenignPathogenic
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
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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.
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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.
Met, very strong: observed 89-nucleotide exon skipping causes a frameshift and termination after four amino acids, consistent with the VCEP's NMD-prone FATKIN splice-defect pathway.
PS3Supporting
PS3 · supporting
Met at Supporting: direct prime editing classified ATM c.6095G>A as Non-functional with High confidence and DeepATM_predicted=No.
PM3Moderate
PM3 · moderate
Met at Moderate: the conservative minimum is 3 PM3 points from affected A-T observations, exceeding the VCEP's 2-point Moderate threshold but not its 4-point Strong threshold.
PP3Supporting
PP3 · supporting
Met: SpliceAI max delta 0.854 exceeds the VCEP PP3 threshold of >=0.2, despite REVEL 0.436 being below the missense threshold of >.7333.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Pathogenic: PVS1 (very strong) plus PS3 and PP3 (supporting) satisfy the ATM VCEP Version 1.6 Rule4; PM3 is additionally moderate.
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
13 / 1,610,458 alleles
gnomAD v4.1: 13 / 1,610,458 alleles. Recorded AF 8.07224e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.78447e-05; MAF= 0.00278%, 7/251394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.15558e-05; MAF= 0.00616%, 7/113718 alleles, homozygotes = 0); grpmax FAF= 2.854e-05.
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.
ACMG/AMP criteria under ClinGen ATM VCEP v1.6, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 7 not met · 2 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is met at very strong strength because variant-specific RNA studies document exon skipping with an out-of-frame premature termination in the VCEP-defined C-terminal FATKIN region.
PM4 and BP3 are not applicable under the ATM VCEP specification.
Within the requested segregation/de novo criteria, PS2, PM6, and BS4 are VCEP-defined not applicable; PP1 remains not assessed because complete biallelic segregation in affected relatives is not documented.
PS3 is met at Supporting because the exact Supplementary Table S1 row is a high-confidence direct prime-editing result classified as Non-functional.
BS3 is not met because the same direct functional result does not show rescue of an ATM-specific feature or radiosensitivity.
The approved-assay calibration file does not itself contain variant-specific results, and no matching approved-assay paper result was established for this variant.
Only the five requested criteria were adjudicated. PS4 is not met because the available case-control counts produce a two-sided Fisher exact p-value of 0.4663, which fails the VCEP's required p-value ≤.05; PP4, PP5, BP5, and BP6 are explicitly not applicable under the ATM VCEP rules.
The VCEP computational criteria were evaluated by their own variant-type branches before considering predictor values.
PP3 is met at Supporting through the VCEP SpliceAI splicing path; BP4 is not met because neither the REVEL nor SpliceAI benign threshold is met; BP7 is not applicable to this missense variant.
Observed splice defects reported in PMID:10980530 and PMID:10330348 were reviewed as variant-specific literature context, but PP3 was assigned from the VCEP-named SpliceAI prediction rather than from observed RNA data.
No criteria match.
Met · 4
PVS1Very strongVCEPMet, very strong: observed 89-nucleotide exon skipping causes a frameshift and termination after four amino acids, consistent with the VCEP's NMD-prone FATKIN splice-defect pathway.
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Reasoning
NM_000051.4:c.6095G>A is a mid-exonic missense change, p.(Arg2032Lys), but patient RNA evidence demonstrates that the alteration is spliceogenic: exon 43 is skipped, the 89-nucleotide loss disrupts the reading frame, and termination occurs after four substituted amino acids. In the VCEP's NM_000051 clinically relevant transcript framework, this lies in the C-terminal FATKIN region; the observed exon-skipping consequence is a frameshift with a premature termination well before the VCEP's p.Ser2_Glu2979 NMD boundary, so the VCEP decision tree assigns full PVS1 weight (very strong). The governing ATM PVS1 file was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K; no exact entry was found, so the call is based on the VCEP's observed-splice-defect pathway and the variant-specific RNA findings rather than a pre-assigned row.
VCEP rule
PVS1_Variable(RNA) shall be used for observed splice defects, whether from canonical +/-1,2 positions or other spliceogenic regions (including mid-exonic missense/synonymous variants that cause splice defects) with baseline weight as per the below decision tree. ... Exon skipping/cryptic site disrupts reading frame, predicted to undergo NMD (p.Ser1893_Glu2979) -> PVS1 (variants listed in D, page 6)
Evidence considered
Case normalization: NM_000051.4:c.6095G>A; NP_000042.3:p.(Arg2032Lys), p.(R2032K); case consequence is missense and the case table identifies exon 41.
ATM_PVS1_1.6.pdf, PVS1 decision-tree text: observed splice defects, including mid-exonic missense variants that cause splice defects, use PVS1_Variable(RNA) with baseline weight from the decision tree; for FATKIN exon skipping that disrupts the reading frame and is predicted to undergo NMD, the result is PVS1.
PMID:10980530, Table 3 (SVAT 1): 6095 G>A is reported with skipping of exon 43 (89 bp), a frameshift, and a stop after four amino-acid substitutions.
PMID:10330348, Table 2 (AT65LA): 6095G>A is reported with 6007del89, exon 43 skipped, frameshift, and truncation.
Still missing
ATM_PVS1_1.6.pdf was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K; no exact entry for this variant was found.
The cited RNA reports demonstrate exon skipping and a premature termination but do not report an NMD-inhibitor experiment; NMD status is therefore inferred from the VCEP decision-tree consequence category.
Older literature numbers this event as exon 43, whereas the case annotation reports exon 41; the VCEP cautions that ATM exon numbering must be reviewed across transcript conventions.
PS3SupportingVCEPMet at Supporting: direct prime editing classified ATM c.6095G>A as Non-functional with High confidence and DeepATM_predicted=No.
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Reasoning
The exact variant row in Sun et al. 2025 Supplementary Table S1 identifies c.6095G>A (ATM R2032K) as Classification=Non-functional, Confidence=High, and DeepATM_predicted=No. Under the governing VCEP curation rule for this file, DeepATM_predicted=No with High confidence represents a direct prime-editing measurement, and Non-functional maps to PS3_Supporting. The VCEP limits PS3 to Supporting for this file. The approved-assay methodology table was also searched under c.6095G>A, p.Arg2032Lys, and p.R2032K, but it is a methodology/calibration table and contains no variant-specific entry; therefore no additional approved-assay strength or conflict is assigned. Patient-material RNA studies reporting exon skipping were reviewed, but the VCEP specifically directs RNA functional evidence to PVS1_Strength(RNA), not PS3.
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, exact row c.6095G>A: genomic position 108315911, ATM missense R2032K, Classification=Non-functional, Confidence=High, DeepATM_predicted=No.
The VCEP's governing file-specific rule treats DeepATM_predicted=No with High, Medium-high, or Medium confidence as direct prime-editing measurement and assigns Classification=Non-functional to PS3_Supporting.
The ClinGen HBOP ATM approved functional-assay supplementary file was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K; no variant-specific row was found, so its assay calibration text was not treated as variant evidence.
PMID:10980530 and PMID:10330348 report variant-associated exon skipping in patient material, but the VCEP PS3 entry directs RNA evidence to PVS1_Strength(RNA); these reports were not used to assign PS3.
Still missing
No variant-specific entry for c.6095G>A, p.Arg2032Lys, or p.R2032K was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-methodology and strength-calibration table rather than a variant-results table.
The approved Mitui 2009, Barone 2009, and Scott 2002 assay papers were not identified as variant-specific sources for this variant in the available evidence bundle.
PM3ModerateVCEPMet at Moderate: the conservative minimum is 3 PM3 points from affected A-T observations, exceeding the VCEP's 2-point Moderate threshold but not its 4-point Strong threshold.
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Reasoning
PM3 applies under the ATM VCEP because this sufficiently rare variant (gnomAD v2.1 grpmax FAF 2.854e-05, below the VCEP's 0.01% limit) is reported in patients with clinically diagnosed ataxia-telangiectasia. The VCEP treats publications claiming a clinical diagnosis of A-T as a confident phenotype. PMID:10330348 reports a heterozygous 6095G>A allele with a second mutant allele (214G>T) in AT65LA, giving 2 points for a confident A-T proband with phase unknown. PMID:16266405 reports 6095G>A in five affected Polish A-T patients, including two siblings, giving at least 1 additional point for a confident affected proband where the second variant/phase is not established. The conservative minimum is therefore 3 PM3 points, which reaches PM3 Moderate (2 points) but not PM3 Strong (4 points) on the VCEP table. PMID:10980530 independently reports 6095G>A in a Swedish A-T family and an exon-skipping consequence, but the available extraction does not establish a separate qualifying phase/variant configuration, so it was not used to increase the conservative point total. The older literature describes 6095G>A as a splice-altering change, whereas the current transcript normalization is p.Arg2032Lys; this transcript/consequence discrepancy requires human review.
VCEP rule
For recessive disorders, detected in trans with a pathogenic variant ... Variant may not exceed general population frequency >0.01%. ... Multiple unrelated cases are additive. ... publications that claim a ‘clinical diagnosis of A-T’ are taken at face value and granted a ‘confident diagnosis. ... Phenotype confident ... Phase unknown ... 2.0 ... Second variant unidentified or VUS ... 1.0 ... PM3_ ... 1.0 2.0 4.0 8.0
Evidence considered
ATM_PM3_BP2_1.6.pdf, page 1: PM3 is for recessive disorders when the variant is detected in trans with a pathogenic variant; its general considerations state that the variant may not exceed general population frequency >0.01% and that multiple unrelated cases are additive.
ATM_PM3_BP2_1.6.pdf, page 1: publications claiming a clinical diagnosis of A-T are taken at face value and granted a confident diagnosis.
ATM_PM3_BP2_1.6.pdf, page 2 table: confident phenotype with phase unknown is 2.0 points per unrelated A-T proband; second variant unidentified or VUS is 1.0 point.
ATM_PM3_BP2_1.6.pdf, page 2 table: PM3 Supporting is 1.0 point, Moderate is 2.0 points, Strong is 4.0 points, and Very Strong is 8.0 points.
gnomAD v2.1: variant present at grpmax FAF 2.854e-05, below the VCEP PM3 general-frequency limit of 0.01%.
PMID:10330348, Table 2 row AT65LA: 6095G>A was heterozygous and 214G>T was listed as the second mutant allele; ATM cDNA showed exon 43 skipping with truncation in an A-T patient cell line.
PMID:16266405, Results/Mutations and Table 2: 6095G>A occurred in 4 of 48 chromosomes from Polish A-T families and affected five patients, including two siblings in family WAR 49.
PMID:10980530, Table 3 SVAT 1 and Table 4: 6095 G>A was reported in a Swedish A-T family and was associated with exon 43 skipping, frameshift, and termination after four substituted amino acids.
Still missing
The ATM_PM3_BP2_1.6.pdf table was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K; no variant-specific pre-assigned row was found.
Exact phase and non-overlapping proband identities are not fully established across the historical reports, so the point total is conservatively capped at 3.
The historical reports describe 6095G>A as exon-skipping/splice-altering, while the case normalization gives NM_000051.4:c.6095G>A (p.Arg2032Lys); transcript equivalence should be confirmed by a human reviewer.
PP3SupportingVCEPMet: SpliceAI max delta 0.854 exceeds the VCEP PP3 threshold of >=0.2, despite REVEL 0.436 being below the missense threshold of >.7333.
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Reasoning
The VCEP PP3 rule covers missense variants through REVEL >.7333 and also permits a splicing path for missense variants using SpliceAI >=0.2. REVEL is 0.436 and therefore does not meet the missense path, but SpliceAI max delta is 0.854 (DS_AL 0.854), which meets the VCEP splicing threshold. The exact VCEP Table S1 row for c.6095G>A (R2032K, exon_41, Missense) reports REVEL 0.436 and DeepATM_predicted=No; its Non-functional classification is not used as the basis for PP3. The separate SpliceAI result is the criterion-bearing computational evidence. The exact c.6095G>A notation was found in the governing full-text table; p.Arg2032Lys and p.R2032K were also searched without an additional matching row.
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 HBOP ATM VCEP v1.6 PP3 Supporting rule: Missense REVEL >.7333, or predicted splice impact via SpliceAI >=0.2 for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites.
SpliceAI Lookup for NM_000051.4:c.6095G>A: DS_AG 0.000, DS_AL 0.854, DS_DG 0.021, DS_DL 0.537; max delta score 0.854.
Sun et al. 2025 Supplementary Table S1, exact row c.6095G>A / R2032K / exon_41 / Missense: CADD.phred 28.6, boostDM_score 0.9557083, EVE_scores_ASM NA, REVEL 0.436, AlphaMissense 0.5083, GnomAD_all_AF 8.07223783544e-06, ClinVar_classification Pathogenic/Likely pathogenic, Classification Non-functional, Confidence High, DeepATM_predicted No. The row is used for the reported REVEL value and as corroboration only; its functional classification is not used to assign PP3.
The ATM full-text search found the exact c.6095G>A row in Suppl_TableS1_PMID 40580951.xlsx; no additional matching row was found for p.Arg2032Lys or p.R2032K.
PS1VCEPNot met: observed exon 43 skipping prevents the missense PS1 path, and ATM_PS1_1.6.pdf has no c.6095G>A, p.Arg2032Lys, or p.R2032K entry.
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Reasoning
PS1 is not met. The governing ATM rule requires the missense path to be used only when a splice defect is ruled out for both alterations. For this variant, PMID:10980530 reports the 6095 G>A alteration with exon 43 skipping, frameshift, and termination after four substituted amino acids; PMID:10330348 independently reports 6095G>A with exon 43 skipping and truncation. The ATM PS1 splicing table was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K and contains no entry for this variant. The exact c.6095G>A row in the VCEP-linked Sun et al. supplementary table is a functional-assessment row, not a PS1 same-amino-acid or splicing-table assignment, so it does not establish PS1.
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.
Evidence considered
ATM_PS1_1.6.pdf: searched c.6095G>A, p.Arg2032Lys, and p.R2032K; no matching PS1 table entry was found.
PMID:10980530, Table 3 (SVAT 1) and Table 4 (recurring mutations): 6095 G>A is reported with skipping of exon 43 (89 bp), frameshift, and stop after four amino-acid substitutions.
PMID:10330348, Table 2 (AT65LA): 6095G>A is reported with 6007del89, exon 43 skipping, and truncation.
Case variant annotation: NM_000051.4:c.6095G>A, NP_000042.3:p.(Arg2032Lys), missense.
Still missing
ATM_PS1_1.6.pdf was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K; no entry for this variant was found.
The literature uses 6095G>A with transcript/exon numbering that conflicts with the current NM_000051.4 missense annotation; transcript-level reconciliation remains for human review.
PS4VCEPNot met: one case and zero controls yielded a two-sided Fisher exact p-value of 0.4663, exceeding the VCEP's ≤0.05 requirement.
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Reasoning
The VCEP requires a case-control p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥2 or a lower 95% confidence interval ≥1.5. PMID:22585167 reports c.6095G>A in 1 of 166 familial pancreatic cancer patients and 0 of 190 spouse controls. From these reported counts, the two-sided Fisher exact p-value is 0.466292134831; 0.466292134831 ≤ 0.05? no. Because the required p-value condition is not met, PS4 is not met regardless of the zero-control odds-ratio boundary estimate.
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
PMID:22585167, Results paragraph 4 and Table 2: c.6095G>A was observed in 1 of 166 familial pancreatic cancer patients and in 0 of 190 spouse controls.
Derived from the reported 1/166 versus 0/190 counts: two-sided Fisher exact p=0.466292134831; explicit comparison: 0.466292134831 ≤ 0.05? no.
PM2VCEPNot met: highest gnomAD subpopulation AF is 0.00110463%, exceeding the VCEP's at-or-below-0.001% PM2 threshold.
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Reasoning
The ATM VCEP applies PM2 Supporting when the frequency is at or below 0.001% in the gnomAD subpopulation with the highest frequency, with an exception for a single allele in one subpopulation absent from all others. The highest all-comers subpopulation AF is 1.1046306115235066e-05 (0.00110463%) in gnomAD v4.1 European (non-Finnish), exceeding the threshold; gnomAD v2.1 is also above it at 6.155577832884856e-05 (0.00615558%). The single-allele exception does not apply because the highest-frequency subpopulation contains 13 alleles in v4.1 and 7 in v2.1.
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: 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.
gnomAD v4.1 all-comers: European (non-Finnish) is the highest-frequency subpopulation at AF 1.1046306115235066e-05 (0.00110463%), 13/1176864 alleles, homozygotes 0.
gnomAD v2.1 all-comers: European (non-Finnish) is the highest-frequency subpopulation at AF 6.155577832884856e-05 (0.00615558%), 7/113718 alleles, homozygotes 0.
The ATM VCEP rule specifies gnomAD subpopulation frequency and does not require a non-cancer subset, so the default all-comers gnomAD entries govern.
BA1VCEPNot met: maximum gnomAD grpmax FAF is 0.002854%, below the VCEP's greater-than-0.5% BA1 threshold.
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Reasoning
The ATM VCEP defines BA1 as a gnomAD group-maximum filtering allele frequency greater than 0.5%. The observed grpmax FAF is 2.854e-05 in gnomAD v2.1 (0.002854%) and 6.16e-06 in gnomAD v4.1 (0.000616%); neither reaches 0.5%.
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 v2.1 all-comers: grpmax FAF 2.854e-05 (0.002854%), based on 7/251394 exome alleles; homozygotes 0.
gnomAD v4.1 all-comers: grpmax FAF 6.16e-06 (0.000616%), based on 13/1610458 total alleles; homozygotes 0.
BS1VCEPNot met: maximum gnomAD grpmax FAF is 0.002854%, below the VCEP's greater-than-0.05% BS1 threshold.
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Reasoning
The ATM VCEP defines BS1 as a gnomAD group-maximum filtering allele frequency greater than 0.05%. The highest observed grpmax FAF is 2.854e-05 in gnomAD v2.1 (0.002854%); gnomAD v4.1 is lower at 6.16e-06 (0.000616%). Neither reaches 0.05%.
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 v2.1 all-comers: grpmax FAF 2.854e-05 (0.002854%), based on 7/251394 exome alleles; homozygotes 0.
gnomAD v4.1 all-comers: grpmax FAF 6.16e-06 (0.000616%), based on 13/1610458 total alleles; homozygotes 0.
BS3VCEPNot met: direct prime editing classified c.6095G>A as Non-functional with High confidence, not as rescuing an ATM-specific feature.
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Reasoning
The exact variant row in Sun et al. 2025 Supplementary Table S1 reports Classification=Non-functional, Confidence=High, and DeepATM_predicted=No, which is direct prime-editing evidence of loss of function rather than rescue of an ATM-specific feature. Therefore the VCEP BS3 rescue rule is not satisfied. The approved-assay methodology table was searched under c.6095G>A, p.Arg2032Lys, and p.R2032K and has no variant-specific entry; no benign functional result or conflicting approved-assay result was identified.
VCEP rule
Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Evidence considered
Sun et al. 2025, Supplementary Table S1, exact row c.6095G>A: Classification=Non-functional, Confidence=High, DeepATM_predicted=No.
The VCEP BS3 rule requires rescue of either an ATM-specific feature or radiosensitivity; the direct row instead reports a non-functional result.
The ClinGen HBOP ATM approved functional-assay supplementary file was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K; no variant-specific row was found.
Still missing
No variant-specific entry for c.6095G>A, p.Arg2032Lys, or p.R2032K was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-methodology and strength-calibration table rather than a variant-results table.
No independent benign functional assay result for this variant was identified in the available evidence bundle.
BP4VCEPNot met: REVEL 0.436 exceeds the BP4 missense cutoff of <=.249 and SpliceAI max delta 0.854 exceeds the no-impact cutoff of <=0.1.
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Reasoning
The VCEP BP4 rule provides a missense path requiring REVEL <=.249 and a splicing path requiring SpliceAI <=0.1. This variant is missense. Its REVEL score is 0.436, above the benign threshold, and its SpliceAI max delta is 0.854, above the no-impact threshold. Neither VCEP BP4 path is met. The exact VCEP Table S1 row for c.6095G>A (R2032K, exon_41, Missense) reports REVEL 0.436; its Non-functional classification is not used to assign BP4.
VCEP rule
* Missense: REVEL score **≤.249**
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
ClinGen HBOP ATM VCEP v1.6 BP4 Supporting rule: Missense REVEL <=.249, or no predicted splice impact via SpliceAI <=0.1.
Local REVEL lookup: score 0.436.
SpliceAI Lookup for NM_000051.4:c.6095G>A: max delta score 0.854, with DS_AL 0.854 and DS_DL 0.537.
Sun et al. 2025 Supplementary Table S1, exact row c.6095G>A / R2032K / exon_41 / Missense: REVEL 0.436; Classification Non-functional, Confidence High, DeepATM_predicted No. The functional classification is not used to assign BP4.
The ATM full-text search found the exact c.6095G>A row in Suppl_TableS1_PMID 40580951.xlsx; no additional matching row was found for p.Arg2032Lys or p.R2032K.
PP1VCEPNot assessed: affected carriers are reported, but no available report documents complete biallelic genotypes and segregation of both proband variants in affected relatives.
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Reasoning
PP1 is applicable only through the ATM VCEP autosomal-recessive path, which requires affected relatives to have both variants identified in the proband. PMID:10980530 reports 6095 G>A in one Swedish AT family and transcript-level exon skipping, while PMID:16266405 reports the variant in affected Polish patients including two siblings; neither extracted report establishes that an affected relative carried both proband variants with documented segregation. The available evidence therefore does not permit assignment of Supporting, Moderate, or Strong PP1. An explicit pedigree-level segregation record with complete biallelic genotypes and phase for affected relatives is required.
VCEP rule
AR Condition: Affected relatives must have both variants identified in proband. ... AR Condition: Segregation in 1 affected relative ... AR Condition: Segregation in 2 affected relatives ... AR Condition: Segregation in ≥3 affected relatives
Evidence considered
The ATM VCEP PP1 rule requires, for the autosomal-recessive condition, that affected relatives have both variants identified in the proband; its strength thresholds are one affected relative for Supporting, two for Moderate, and at least three for Strong.
Laake et al. 2000, PMID:10980530, Table 3 SVAT 1, reports 6095 G>A in one Swedish ataxia-telangiectasia family inherited through the paternal allele and documents exon 43 skipping, but the extracted record does not establish complete biallelic genotypes and segregation in affected relatives.
Mitui et al. 2005, PMID:16266405, Results/Mutations and Table 2, reports 6095G>A in four of 48 analyzed chromosomes and in five affected patients including two siblings in family WAR 49, but the extracted record does not document that affected relatives carried both variants identified in the proband or provide a segregation count.
Still missing
Pedigree-level segregation data for affected relatives
Confirmation that each counted affected relative carries both variants identified in the proband
Parental testing or phase information for the complete biallelic genotypes
BP2Not assessed: no qualifying unaffected adult observation with documented phase, zygosity, and absence of A-T is available for the VCEP's BP2 point assignment.
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Reasoning
The ATM VCEP BP2 rule requires an observation in an unaffected non-A-T adult with the relevant pathogenic-variant configuration and age/phenotype context. PMID:22585167 reports p.R2032K among 166 familial pancreatic-cancer patients and states that it had previously been observed in A-T patients, but it does not establish that the carrier was an unaffected adult without A-T, the phase with another pathogenic ATM variant, or the required zygosity. No other available evidence establishes a qualifying BP2 observation, so BP2 cannot be evaluated without substituting an unapproved generic rule.
Evidence considered
ATM_PM3_BP2_1.6.pdf, page 2: 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 table's unaffected non-A-T adult context requires a qualifying adult observation.
ATM_PM3_BP2_1.6.pdf, page 2 table: BP2 point assignment requires confirmed in trans, phase unknown, or homozygous categories, with -1 point Supporting, -2 points Moderate, and ≤-4 points Strong.
PMID:22585167, Results paragraph 4/Table 2: c.6095G>GA; p.R2032K was identified in one of 166 familial pancreatic-cancer patients and in none of 190 spouse controls, and was described as previously observed in A-T patients; the report does not provide the required unaffected-A-T, phase, or zygosity details.
Still missing
The ATM_PM3_BP2_1.6.pdf table was searched for c.6095G>A, p.Arg2032Lys, and p.R2032K; no variant-specific pre-assigned row was found.
No available report documents an unaffected non-A-T adult over 18 years old carrying this variant with the phase and pathogenic-variant configuration required by the ATM VCEP BP2 table.
Not applicable · 15· recorded as not applicableShow reasons ▾Hide reasons ▴PS2VCEPNot applicable: the ATM VCEP directs that PS2 not be used because informative de novo occurrences have not been observed.
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Reasoning
PS2 is not applicable under the ATM VCEP because the specification states that informative de novo occurrences have not been observed and directs that PS2 not be used for autosomal dominant or autosomal recessive disease.
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
The ATM VCEP CSPEC entry for PS2 marks it not applicable and states: 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.
PM1VCEPNot applicable: the ATM VCEP explicitly marks PM1 Not Applicable, and no authoritative ATM domain-table entry is present.
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Reasoning
The ATM VCEP criterion entry marks PM1 as Not Applicable. The authoritative vcep_materials.json domain_tables key for ATM is empty, so no approved critical-domain list is available to support a separate PM1 determination.
VCEP rule
Not Applicable
Evidence considered
ATM VCEP v1.6 CSPEC criterion entry: PM1 applicability is Not Applicable.
vcep_materials.json: domain_tables is empty for ATM.
PM4N/ANot applicable: PM4 is restricted by the ATM VCEP to stop-loss variants, whereas c.6095G>A is a missense substitution.
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Reasoning
The ATM VCEP specifies PM4 only for stop-loss variants. This variant is annotated as a missense substitution, p.(Arg2032Lys), and is not a stop-loss variant; the observed splice consequence does not change the criterion's stated applicability.
VCEP rule
Use for stop-loss variants.
Evidence considered
ATM CSPEC PM4 entry: the rule is limited to stop-loss variants.
Case normalization and consequence: NM_000051.4:c.6095G>A, NP_000042.3:p.(Arg2032Lys), missense.
PM5N/ANot applicable: the ATM PM5 rule is limited to qualifying NMD-prone truncating variants, whereas c.6095G>A is missense.
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Reasoning
PM5 is not applicable because the ATM VCEP v1.6 rule is restricted to NMD-prone truncating DNA variants receiving PVS1 at Very Strong, or observed NMD-prone truncating splice variants receiving PVS1(RNA) at Very Strong with high-quality RNA data. This case is a missense variant.
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 ... Splice Variants: Apply only to observed (not predicted) NMD-prone, truncating variants receiving PVS1(RNA) (must be at VeryStrong with high-quality RNA data) with premature termination codons upstream of p.Leu3048. This is not applicable for predicted splice impact without RNA data or PVS1(RNA) at reduced strength.
Evidence considered
ATM VCEP v1.6 PM5 rule: DNA and splice paths require NMD-prone truncating variants and Very Strong PVS1/PVS1(RNA).
Case variant annotation: NM_000051.4:c.6095G>A is missense.
PM6VCEPNot applicable: the ATM VCEP directs that PM6 not be used because informative de novo occurrences have not been observed.
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Reasoning
PM6 is not applicable under the ATM VCEP because the specification states that informative de novo occurrences have not been observed and directs that PM6 not be used for autosomal dominant or autosomal recessive disease.
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
The ATM VCEP CSPEC entry for PM6 marks it not applicable and states: 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.
PP4VCEPNot applicable: the VCEP excludes PP4 for both ATM-related breast cancer and ataxia-telangiectasia phenotype assessment.
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Reasoning
The ATM VCEP marks PP4 not applicable: it excludes PP4 for autosomal dominant ATM-related breast cancer because breast cancer has multiple genetic etiologies and no readily distinguishing features, and excludes it as a separate line of evidence 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 PP4 instructions: autosomal dominant PP4 is not used for breast cancer because of genetic heterogeneity and absent distinguishing features; autosomal recessive PP4 is not used separately because it is built into the Ataxia Telangiectasia PM3/BP2 table.
PP5VCEPNot applicable: the ATM VCEP explicitly prohibits use of PP5 for this VCEP.
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Reasoning
The ATM VCEP marks PP5 not applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
ATM VCEP PP5 entry: applicability is Not Applicable for this VCEP and its instruction states that the criterion is not for use.
BS4VCEPNot applicable: the ATM VCEP states that informative lack-of-segregation instances in ataxia-telangiectasia families are too rare to receive weight.
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Reasoning
BS4 is marked not applicable by the ATM VCEP. The VCEP specifically states that informative lack-of-segregation instances in ataxia-telangiectasia families are too rare to receive weight.
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
The ATM VCEP CSPEC entry for BS4 marks it not applicable and states: 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.
BP3VCEPNot applicable: the ATM VCEP marks BP3 not applicable, and this variant is a missense substitution rather than a qualifying repeat-region in-frame indel.
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Reasoning
The ATM CSPEC marks BP3 as not applicable. The variant is a missense substitution with documented splice disruption and is not an in-frame deletion or insertion in a repetitive region under an applicable BP3 pathway.
VCEP rule
Not Applicable
Evidence considered
ATM CSPEC BP3 entry: applicability is Not Applicable.
Case normalization and consequence: NM_000051.4:c.6095G>A, NP_000042.3:p.(Arg2032Lys), missense.
BP5VCEPNot applicable: the ATM VCEP instructs reviewers not to use BP5 because ATM's low penetrance permits frequent co-occurring pathogenic variants.
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Reasoning
The ATM VCEP marks BP5 not applicable and instructs that it should not be used because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference, while ATM's low penetrance makes other pathogenic variants more likely to occur concurrently.
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 BP5 instructions: do not use BP5 because multiple pathogenic variants can occur without a noticeable phenotype difference and ATM has low penetrance.
BP6VCEPNot applicable: the ATM VCEP explicitly prohibits use of BP6 for this VCEP.
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Reasoning
The ATM VCEP marks BP6 not applicable for this VCEP and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
ATM VCEP BP6 entry: applicability is Not Applicable for this VCEP and its instruction states that the criterion is not for use.
BP7N/ANot applicable: BP7 covers synonymous or qualifying deep intronic variants, whereas c.6095G>A is a missense substitution in exon 41.
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Reasoning
BP7 is limited by the VCEP to synonymous and qualifying deep intronic variants, or to observed absence of an aberrant RNA defect for silent or intronic variants. This variant is a missense substitution in exon 41, so BP7 is outside its governing scope.
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 facts: NM_000051.4:c.6095G>A, NP_000042.3:p.(Arg2032Lys), missense, exon 41.
The ATM full-text search found c.6095G>A in the governing Supplementary Table S1; the BP7 scope excludes this missense variant regardless of available splice predictions.
AF 8.1e-06 · 13 / 1,610,458 alleles · 0 hom · FAF 6.2e-06
European (non-Finnish)13 / 1,176,864
1.1e-05
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 2.8e-05 · 7 / 251,394 alleles · 0 hom · FAF 2.9e-05
European (non-Finnish)7 / 113,718
6.2e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.07224e-06; MAF= 0.00081%, 13/1610458 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.10463e-05; MAF= 0.00110%, 13/1176864 alleles, homozygotes = 0); grpmax FAF= 6.16e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.78447e-05; MAF= 0.00278%, 7/251394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.15558e-05; MAF= 0.00616%, 7/113718 alleles, homozygotes = 0); grpmax FAF= 2.854e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -88 bp
0.854
SpliceAI acceptor gainat +0 bp
0.000
SpliceAI donor lossat +0 bp
0.537
SpliceAI donor gainat +25 bp
0.021
Pangolin splice lossmagnitude shown
-0.718
Pangolin splice gain
0.024
Other predictors
REVEL
0.436
BayesDel
0.014
How the predictions were used
PP3SupportingVCEPMet: SpliceAI max delta 0.854 exceeds the VCEP PP3 threshold of >=0.2, despite REVEL 0.436 being below the missense threshold of >.7333.
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Reasoning
The VCEP PP3 rule covers missense variants through REVEL >.7333 and also permits a splicing path for missense variants using SpliceAI >=0.2. REVEL is 0.436 and therefore does not meet the missense path, but SpliceAI max delta is 0.854 (DS_AL 0.854), which meets the VCEP splicing threshold. The exact VCEP Table S1 row for c.6095G>A (R2032K, exon_41, Missense) reports REVEL 0.436 and DeepATM_predicted=No; its Non-functional classification is not used as the basis for PP3. The separate SpliceAI result is the criterion-bearing computational evidence. The exact c.6095G>A notation was found in the governing full-text table; p.Arg2032Lys and p.R2032K were also searched without an additional matching row.
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 HBOP ATM VCEP v1.6 PP3 Supporting rule: Missense REVEL >.7333, or predicted splice impact via SpliceAI >=0.2 for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites.
SpliceAI Lookup for NM_000051.4:c.6095G>A: DS_AG 0.000, DS_AL 0.854, DS_DG 0.021, DS_DL 0.537; max delta score 0.854.
Sun et al. 2025 Supplementary Table S1, exact row c.6095G>A / R2032K / exon_41 / Missense: CADD.phred 28.6, boostDM_score 0.9557083, EVE_scores_ASM NA, REVEL 0.436, AlphaMissense 0.5083, GnomAD_all_AF 8.07223783544e-06, ClinVar_classification Pathogenic/Likely pathogenic, Classification Non-functional, Confidence High, DeepATM_predicted No. The row is used for the reported REVEL value and as corroboration only; its functional classification is not used to assign PP3.
The ATM full-text search found the exact c.6095G>A row in Suppl_TableS1_PMID 40580951.xlsx; no additional matching row was found for p.Arg2032Lys or p.R2032K.
BP4VCEPNot met: REVEL 0.436 exceeds the BP4 missense cutoff of <=.249 and SpliceAI max delta 0.854 exceeds the no-impact cutoff of <=0.1.
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Reasoning
The VCEP BP4 rule provides a missense path requiring REVEL <=.249 and a splicing path requiring SpliceAI <=0.1. This variant is missense. Its REVEL score is 0.436, above the benign threshold, and its SpliceAI max delta is 0.854, above the no-impact threshold. Neither VCEP BP4 path is met. The exact VCEP Table S1 row for c.6095G>A (R2032K, exon_41, Missense) reports REVEL 0.436; its Non-functional classification is not used to assign BP4.
VCEP rule
* Missense: REVEL score **≤.249**
* Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
ClinGen HBOP ATM VCEP v1.6 BP4 Supporting rule: Missense REVEL <=.249, or no predicted splice impact via SpliceAI <=0.1.
Local REVEL lookup: score 0.436.
SpliceAI Lookup for NM_000051.4:c.6095G>A: max delta score 0.854, with DS_AL 0.854 and DS_DL 0.537.
Sun et al. 2025 Supplementary Table S1, exact row c.6095G>A / R2032K / exon_41 / Missense: REVEL 0.436; Classification Non-functional, Confidence High, DeepATM_predicted No. The functional classification is not used to assign BP4.
The ATM full-text search found the exact c.6095G>A row in Suppl_TableS1_PMID 40580951.xlsx; no additional matching row was found for p.Arg2032Lys or p.R2032K.
BP7N/ANot applicable: BP7 covers synonymous or qualifying deep intronic variants, whereas c.6095G>A is a missense substitution in exon 41.
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Reasoning
BP7 is limited by the VCEP to synonymous and qualifying deep intronic variants, or to observed absence of an aberrant RNA defect for silent or intronic variants. This variant is a missense substitution in exon 41, so BP7 is outside its governing scope.
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 facts: NM_000051.4:c.6095G>A, NP_000042.3:p.(Arg2032Lys), missense, exon 41.
The ATM full-text search found c.6095G>A in the governing Supplementary Table S1; the BP7 scope excludes this missense variant regardless of available splice predictions.
SpliceAI predicts possible splice impact for this variant (max delta score = 0.85). REVEL score = 0.436. BayesDel score = 0.0141465.
8 paper records listed. 4 cited in the classification.
Cited in the classification
Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.
Teraoka SN et al. · 1999 Jun
The paper reports ATM 6095G>A in patient cell line AT65LA. ATM cDNA analysis showed deletion of 89 nucleotides, corresponding to exon 43 skipping, with a predicted frameshift and truncation.
→ PVS1 · very strong→ PM3 · moderateNames this variant
Location Table 2, row for AT65LA; Results section, Mutations in ATM cDNA
Context ATM mutation analysis in 49 ataxia-telangiectasia patient cell lines using protein-truncation testing and SSCP of cDNA, followed by genomic-DNA and cDNA sequencing to assess splicing consequences.
Characterization of ATM mutations in 41 Nordic families with ataxia telangiectasia.
Laake K et al. · 2000 Sep
The paper explicitly reports ATM 6095 G>A in one Swedish ataxia-telangiectasia family. Transcript analysis showed skipping of exon 43, an 89-bp deletion, a frameshift, and termination after four substituted amino acids.
→ PVS1 · very strong→ PM3 · moderateNames this variant
Context ATM mutation screening in 41 Nordic ataxia-telangiectasia families using cDNA and genomic PCR, heteroduplex/fragment-length analysis, protein truncation testing, and bidirectional sequencing; transcript consequences were assessed by cDNA analysis.
ATM gene founder haplotypes and associated mutations in Polish families with ataxia-telangiectasia.
Mitui M et al. · 2005 Nov
The paper reports ATM 6095G>A in four of 48 analyzed chromosomes from Polish ataxia-telangiectasia families and in five affected patients, including two siblings in family WAR 49; it does not document that affected relatives carried both variants identified in the proband or provide a qualifying segregation count.
The second and third most common mutations, 5932G>T and 6095G>A, were each found in 5 and 4 chromosomes (10% and 8%), in association with Haplotypes [D] and [B], respectively.
Location Results, Mutations; Table 2; Results, Genotypes versus Phenotypes; Discussion
Context Mutation screening and haplotype analysis of 24 unrelated Polish ataxia-telangiectasia families; methods included protein truncation testing, cDNA SSCP, genomic DNA dHPLC, bidirectional sequencing, STR haplotyping, and SNP haplotyping.
Sun et al. 2025
The associated Sun et al. 2025 source is represented in this case by its exact Supplementary Table S1 row: ATM c.6095G>A is classified Non-functional with High confidence and DeepATM_predicted=No, indicating direct assay evidence rather than a model-only prediction.
Context Prime-editing functional assessment of ATM SNVs with a DeepATM_predicted field distinguishing direct measurements from computational predictions.
Other recorded publications
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.
ATM mutations in patients with hereditary pancreatic cancer.
Roberts NJ et al. · 2012
The paper explicitly reports ATM c.6095G>GA; p.R2032K, corresponding to the queried c.6095G>A variant, in one of 166 familial pancreatic cancer patients and in none of 190 spouse controls. It provides the case-control counts but no variant-specific functional, segregation, or tumor analysis for p.R2032K.
Four variants: c.3214G>GT; p.E1072X, c.6095G>GA; p.R2032K, IVS41-1G>GT and c.3801delG (Table 2) previously observed in patients with ataxia-telangiectasia (6–9) were identified in the 166 pancreatic cancer patients, while none were identified in the controls.
Results, paragraph 4; Table 2
Ten new ATM alterations in Polish patients with ataxia-telangiectasia.
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.
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= 8.07224e-06; MAF= 0.00081%, 13/1610458 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.10463e-05; MAF= 0.00110%, 13/1176864 alleles, homozygotes = 0); grpmax FAF= 6.16e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.78447e-05; MAF= 0.00278%, 7/251394 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.15558e-05; MAF= 0.00616%, 7/113718 alleles, homozygotes = 0); grpmax FAF= 2.854e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (22 clinical laboratories) and as Likely pathogenic (5 clinical laboratories) and as pathogenic (2 clinical laboratories). (ClinVarID = 181974)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.85). REVEL score = 0.436. BayesDel score = 0.0141465.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.