Five-step scale from benign to pathogenic. Select a step to read what it means.
Scenario
BenignPathogenic
Not classified yet.Select a step to read what it means.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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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Criteria may be applied incorrectly, sources may be misread, and a
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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 at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the ATM PM2 threshold of ≤0.001%.
Benign criteria applied · 1
BS3Supporting
BS3 · supporting
Met, provisionally: direct prime-editing classified c.182T>G as Functional with Medium-high confidence, consistent with retained ATM function and BS3 Supporting.
Recorded classification: Not classified
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.6 v1.6 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BS3 supporting; maps to Uncertain Significance - Conflicting Evidence.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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: 2 met · 5 not met · 5 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
For ATM, the governing Version 1.6 framework excludes PS2, PM6, and BS4; PP1 is potentially applicable but requires documented affected-relative segregation that is absent from the available case evidence.
The exact Table S1 entry is direct functional measurement (DeepATM_predicted=No) and is classified Functional with Medium-high confidence, supporting benign functional evidence rather than pathogenic functional loss.
The ATM VCEP-approved calibration file was searched under c.182T>G, p.Phe61Cys, and p.F61C; it contains no variant-specific entry and only calibrates three approved kinase assays and the approved Mitui radiosensitivity assay.
BS3 Supporting is recorded provisionally with needs_human_review=true because the direct prime-editing assay is outside the current approved assay set; PS3 is not met because the result is Functional rather than non-functional.
The ClinGen HBOP ATM VCEP version 1.6 governs this assessment.
PS4 remains not assessed because variant-specific case-control enrichment statistics are absent.
PP4, PP5, BP5, and BP6 are excluded or not applicable under the ATM VCEP; no expert-panel ClinVar assertion is present.
The variant is missense, so PP3 and BP4 use REVEL only; REVEL 0.62 meets neither the ATM VCEP PP3 threshold (>0.7333) nor the BP4 threshold (<=0.249).
BP7 is not applicable because the variant is not synonymous or qualifying deep-intronic.
Population evidence supports PM2 at supporting strength because the variant is absent from gnomAD v2.1 and v4.1.
BA1 and BS1 are not met because the variant is not observed at their ATM VCEP frequency thresholds.
BS2 is not applicable under the ATM VCEP because ATM-related cancer predisposition has incomplete penetrance.
No criteria match.
Met · 2
PM2SupportingMet at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the ATM PM2 threshold of ≤0.001%.
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Reasoning
The ATM VCEP specifies PM2 at supporting strength when the variant frequency is at or below 0.001% in the gnomAD subpopulation with the highest frequency, with a single-observation exception. NM_000051.4:c.182T>G (p.Phe61Cys) is absent from gnomAD v2.1 and gnomAD v4.1, including the relevant default all-comers population datasets, so its observed frequency is 0 and satisfies the ATM PM2-supporting rule.
Rule
Frequency ≤0.001% in gnomAD subpopulation with the highest frequency; PM2 Supporting; ATM VCEP v1.6
Evidence considered
ClinGen HBOP ATM VCEP version 1.6 specifies PM2 at supporting strength for frequency ≤0.001% in the highest-frequency gnomAD subpopulation.
The variant is absent from gnomAD v2.1 and gnomAD v4.1, giving an observed frequency of zero in the available default population datasets.
BS3SupportingMet, provisionally: direct prime-editing classified c.182T>G as Functional with Medium-high confidence, consistent with retained ATM function and BS3 Supporting.
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Reasoning
The exact variant is directly measured in Sun et al. Table S1 as Functional with Confidence=Medium-high and DeepATM_predicted=No, supporting retained ATM function rather than a damaging functional effect. This direction is consistent with the ATM VCEP BS3 Supporting concept for rescue of either an ATM-specific feature or radiosensitivity, but the VCEP-approved assay table does not include the newer prime-editing assay and contains no variant-specific result for c.182T>G. BS3 Supporting is therefore a provisional application of the pre-assigned Functional result and requires human review for assay acceptance under the current VCEP specification.
Rule
ATM VCEP v1.6 BS3: Supporting when a variant rescues either an ATM-specific feature or radiosensitivity; Moderate when it rescues both.
Evidence considered
The exact variant row in Table S1 is chr11:108227885 T>G, c.182T>G, F61C, Missense, with Classification Functional, Confidence Medium-high, and DeepATM_predicted No.
The direct-measurement flag DeepATM_predicted=No distinguishes this row from computational extrapolations and supports treating it as direct functional evidence.
The ATM VCEP BS3 rule assigns Supporting when a variant rescues either an ATM-specific feature or radiosensitivity, and Moderate when it rescues both.
The VCEP calibration table lists the approved assay methodologies and proposed BS3 Supporting calibration but has no row reporting the current variant; the newer prime-editing assay therefore requires human acceptance review.
Still missing
No variant-specific c.182T>G, p.Phe61Cys, or p.F61C entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-methodology and calibration table, not a per-variant results table.
The assay producing the Functional result is not one of the three ATM VCEP-approved assays, so human review is required to confirm that BS3 Supporting can be applied under the current VCEP specification.
PS3Not met: Table S1 directly measured c.182T>G as Functional, not a failure of ATM function, but the assay is outside the VCEP-approved assay set.
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Reasoning
The governing ATM VCEP PS3 specification assigns pathogenic functional evidence when a variant fails rescue of an ATM-specific feature, with moderate strength requiring failure of both an ATM-specific feature and radiosensitivity and supporting strength requiring failure of the ATM-specific feature alone. The exact variant is present in Sun et al. Table S1 as c.182T>G (p.F61C), classified Functional with Confidence=Medium-high and DeepATM_predicted=No, which is direct prime-editing functional evidence inconsistent with a loss-of-function result. However, this assay is not one of the three ATM VCEP-approved kinase assays and no variant-specific result was found in the approved-assay calibration table; therefore PS3 is not met under the current VCEP specification, pending human review of whether the newer assay can be accepted.
Rule
ATM VCEP v1.6 PS3: Supporting for failure to rescue an ATM-specific feature alone; Moderate for failure to rescue both an ATM-specific feature and radiosensitivity; do not use Strong.
Evidence considered
The exact variant row in Table S1 is chr11:108227885 T>G, c.182T>G, F61C, Missense, with Combined_score -0.130965363199676, Classification Functional, Confidence Medium-high, and DeepATM_predicted No.
The ATM VCEP PS3 rule states that PS3 Supporting is for failure to rescue an ATM-specific feature and PS3 Moderate requires failure of both an ATM-specific feature and radiosensitivity; PS3 Strong is not used.
The ATM VCEP-approved assay table lists only Mitui 2009 (PMID:18634022), Barone 2009 (PMID:19431188), and Scott 2002 (PMID:11805335) for kinase-activity calibration, and explicitly does not provide variant-specific results for the current variant.
Because DeepATM_predicted=No, the Table S1 classification represents direct prime-editing measurement rather than a model extrapolation; because the assay is not among the VCEP-approved assays, the result requires human review and is not silently assigned a VCEP PS3 strength.
Still missing
No variant-specific c.182T>G, p.Phe61Cys, or p.F61C entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-methodology and calibration table, not a per-variant results table.
The direct functional result is from a newer prime-editing assay that the ATM VCEP has not calibrated as an approved PS3 assay; human adjudication is required before assigning PS3 strength.
PP3Not met: REVEL 0.62 is below the ATM VCEP PP3 Supporting threshold of >0.7333 for missense variants.
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Reasoning
This is a missense variant, so the ATM VCEP missense REVEL path applies and SpliceAI is not used. The governing ATM VCEP v1.6 specifies PP3 Supporting for REVEL >0.7333. The exact c.182T>G / F61C row in the governing Sun et al. Table S1 reports REVEL 0.62, which is below the VCEP threshold; therefore PP3 is not met. The row's Functional / Medium-high / DeepATM_predicted=No fields are direct functional-screen outputs, not a calibrated PP3 code, and are not used to assign this computational criterion.
The ATM VCEP v1.6 specification assigns PP3 Supporting to missense variants with REVEL >0.7333.
The local REVEL lookup reports a score of 0.62 for NM_000051.4:c.182T>G (p.Phe61Cys/p.F61C).
The exact c.182T>G row in Suppl_TableS1_PMID 40580951 reports F61C, Missense, REVEL 0.62, Classification Functional, Confidence Medium-high, and DeepATM_predicted No; these latter fields are functional-screen results and were not converted into PP3.
BA1Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the ATM VCEP BA1 threshold of >0.5%.
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Reasoning
The ATM VCEP defines BA1 as a gnomAD group maximum filtering allele frequency greater than 0.5%. NM_000051.4:c.182T>G (p.Phe61Cys) is absent from gnomAD v2.1 and gnomAD v4.1, so the BA1 frequency threshold is not met.
Rule
Grpmax Filtering AF >0.5% in gnomAD; ATM VCEP v1.6
Evidence considered
ClinGen HBOP ATM VCEP version 1.6 specifies BA1 for gnomAD group maximum filtering allele frequency >0.5%.
The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; no population allele frequency is available to approach the BA1 threshold.
BS1Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the ATM VCEP BS1 threshold of >0.05%.
Details ▾Hide ▴
Reasoning
The ATM VCEP defines BS1 as a gnomAD group maximum filtering allele frequency greater than 0.05%. NM_000051.4:c.182T>G (p.Phe61Cys) is absent from gnomAD v2.1 and gnomAD v4.1, so it does not meet the BS1 threshold.
Rule
Grpmax Filtering AF >0.05% in gnomAD; ATM VCEP v1.6
Evidence considered
ClinGen HBOP ATM VCEP version 1.6 specifies BS1 for gnomAD group maximum filtering allele frequency >0.05%.
The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; no population allele frequency supports BS1.
BP4Not met: REVEL 0.62 exceeds the ATM VCEP BP4 Supporting threshold of <=0.249 for missense variants.
Details ▾Hide ▴
Reasoning
This is a missense variant, so BP4 is evaluated only through the ATM VCEP missense REVEL path; the SpliceAI result is not substituted. The governing ATM VCEP v1.6 specifies BP4 Supporting for REVEL <=0.249. The exact c.182T>G / F61C row and the local REVEL lookup both report 0.62, which is above 0.249 and lies in the non-benign gray zone; therefore BP4 is not met. No SpliceAI score is available, but that missing splice result does not alter the missense BP4 conclusion.
The ATM VCEP v1.6 specification assigns BP4 Supporting to missense variants with REVEL <=0.249.
The local REVEL lookup reports a score of 0.62 for NM_000051.4:c.182T>G (p.Phe61Cys/p.F61C), so it does not meet the BP4 cutoff.
The exact c.182T>G row in Suppl_TableS1_PMID 40580951 independently reports REVEL 0.62.
SpliceAI returned no score, which is missing data rather than evidence for BP4; in any event, SpliceAI is not the applicable BP4 path for this missense variant.
PS1Not assessed: no established p.Phe61Cys comparator was identified, and SpliceAI returned no score to rule out a splice defect.
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Reasoning
The governing ATM VCEP PS1 specification permits strong PS1 for a missense change only when the same amino-acid change is established as pathogenic or likely pathogenic and splicing is ruled out for both variants. Direct searches of ATM_PS1_1.5.pdf.txt for c.182T>G, p.Phe61Cys, and p.F61C found no variant entry. The case evidence reports no ClinVar record, no relevant literature PMID, and no SpliceAI score; therefore neither a qualifying same-amino-acid comparator nor complete splice exclusion is available.
Rule
ATM VCEP PS1: use for missense changes only when splicing is ruled out for both alterations; otherwise use the ATM PS1 splicing table when its prerequisites are met.
Evidence considered
ATM PS1 VCEP v1.5 states that missense PS1 requires the same amino-acid change as an established pathogenic variant and requires splicing to be ruled out for both alterations.
Searches of ATM_PS1_1.5.pdf.txt for c.182T>G, p.Phe61Cys, and p.F61C found no entry for this variant.
ClinVar reports no record for NM_000051.4:c.182T>G, and the case literature packet contains no relevant PMID.
SpliceAI returned no score; this is missing data rather than evidence of absent splice impact.
Still missing
ATM_PS1_1.5.pdf.txt contains no entry for c.182T>G, p.Phe61Cys, or p.F61C.
No established pathogenic or likely pathogenic same-amino-acid comparator is available in the case evidence.
SpliceAI returned no score, so splice exclusion is incomplete.
PS4Not assessed: no case-control p-value, odds ratio, relative risk, hazard ratio, or lower 95% confidence interval is available for this variant.
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Reasoning
The governing ClinGen HBOP ATM VCEP version 1.6 permits PS4 at Strong only for case-control studies with p-value <=.05 and either odds ratio, hazard ratio, or relative risk >=2 or lower 95% CI >=1.5. The consolidated evidence contains no case-control cohort, affected-versus-control counts, p-value, effect estimate, or confidence interval for NM_000051.4:c.182T>G (ATM p.Phe61Cys), so PS4 cannot be assessed. No numeric threshold conclusion is made because the required case-control metric is unavailable.
Rule
Case-control studies; p-value <=.05 and (Odds ratio, hazard ratio, or relative risk >=2 or lower 95% CI >=1.5).
Evidence considered
ClinGen HBOP ATM VCEP version 1.6 states: "Case-control studies; p-value <=.05 and (Odds ratio, hazard ratio, or relative risk >=2 or lower 95% CI >=1.5)."
No variant-specific case-control prevalence or enrichment result was present in the reviewed case evidence.
Still missing
A variant-specific case-control study or calibrated affected-case/control evidence with p-value and effect estimate or lower 95% confidence interval is unavailable.
PM3Not assessed: no affected Ataxia-Telangiectasia proband or qualifying pathogenic allele in trans was documented, so the VCEP PM3 point total is unavailable.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM PM3/BP2 specification requires affected Ataxia-Telangiectasia proband observations with the variant in trans with a VCEP-classified pathogenic or likely pathogenic ATM variant, phase-unknown co-occurrence, an unidentified/VUS second allele, or qualifying homozygosity. The case evidence contains no affected-proband observation, phase information, or qualifying second ATM allele for NM_000051.4:c.182T>G (NP_000042.3:p.(Phe61Cys)/p.(F61C)); therefore no PM3 points can be assigned. Searches of ATM_PM3_BP2_1.5.pdf found no entry for c.182T>G, p.Phe61Cys, or p.F61C. The variant is present in the separate Suppl_TableS1_PMID 40580951 functional table, but that entry does not provide affected-proband or allelic-phase evidence and cannot establish PM3.
Rule
ATM VCEP PM3 points: confident A-T phenotype = 4.0 confirmed in trans, 2.0 phase unknown, 1.0 second variant unidentified or VUS, 2.0 qualifying homozygous individual; consistent phenotype = half these values. PM3 Supporting = 1.0 point, Moderate = 2.0, Strong = 4.0, Very Strong = 8.0.
Evidence considered
The ATM VCEP PM3 table assigns points only from unrelated A-T probands: confident phenotype 4.0 confirmed in trans, 2.0 phase unknown, 1.0 with an unidentified or VUS second variant, or 2.0 for qualifying homozygosity; consistent phenotype receives half those values.
The case evidence reports no literature PMIDs and provides no affected-proband, second-allele, phase, or homozygosity observation for c.182T>G/p.Phe61Cys/p.F61C.
The exact-variant search found c.182T>G/F61C in Suppl_TableS1_PMID 40580951, but that row is a functional-table entry and contains no allelic-phase or affected-proband evidence relevant to PM3.
Still missing
No affected-proband observation with NM_000051.4:c.182T>G was identified in the case evidence.
No pathogenic or likely pathogenic ATM variant in trans, phase-unknown, cis, or homozygous affected-patient observation was documented.
ATM_PM3_BP2_1.5.pdf was searched for c.182T>G, p.Phe61Cys, and p.F61C; no entry for this variant was found.
Sources
vcep_atm_pm3_bp2_1_5
PP1Not assessed: no affected-relative segregation, parental testing, pedigree, or meiosis data are documented for this variant.
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Reasoning
The governing ClinGen HBOP ATM Version 1.6 specification permits PP1 for autosomal-recessive segregation: Supporting for one affected relative, Moderate for two, and Strong for at least three. The available case evidence contains no documented affected relatives, parental testing results, family pedigree, or meiosis count for NM_000051.4:c.182T>G, so segregation cannot be assigned.
Rule
ATM Version 1.6 PP1: autosomal-recessive segregation in 1 affected relative = Supporting; 2 affected relatives = Moderate; at least 3 affected relatives = Strong.
Evidence considered
The ATM Version 1.6 framework specifies PP1 Supporting for segregation in one affected relative, Moderate for two, and Strong for at least three affected relatives in the autosomal-recessive context.
No proband-family segregation, parental testing, affected-relative, or meiosis evidence was available in the reviewed case materials.
Still missing
Documented segregation data from affected relatives, including their phenotypes, variant genotypes, and phase/relationship information are needed.
BP2Not assessed: no unaffected adult carrying the variant with a qualifying pathogenic ATM allele in trans was documented, so the VCEP BP2 point total is unavailable.
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Reasoning
The governing ClinGen HBOP ATM PM3/BP2 specification requires an unaffected non-Ataxia-Telangiectasia adult carrying the variant with a VCEP-classified pathogenic or likely pathogenic ATM variant in trans, with phase and setting determining the negative points. The case evidence contains no unaffected adult co-occurrence, pathogenic or likely pathogenic ATM allele in trans, phase information, or qualifying homozygous observation for NM_000051.4:c.182T>G (NP_000042.3:p.(Phe61Cys)/p.(F61C)); therefore no BP2 points can be assigned. Searches of ATM_PM3_BP2_1.5.pdf found no entry for c.182T>G, p.Phe61Cys, or p.F61C. The variant is present in the separate Suppl_TableS1_PMID 40580951 functional table, but that entry does not provide unaffected-person co-occurrence or allelic-phase evidence and cannot establish BP2.
Rule
ATM VCEP BP2 points: unaffected non-A-T adult with a P/LP ATM variant = -4.0 confirmed in trans or -2.0 phase unknown; homozygous maximum -2.0, with -2.0 laboratory setting or -1.0 database setting. BP2 Supporting = -1.0 point, Moderate = -2.0, Strong = <= -4.0.
Evidence considered
The ATM VCEP BP2 table assigns negative points per unaffected non-A-T adult with a pathogenic or likely pathogenic ATM variant: -4.0 confirmed in trans, -2.0 phase unknown, and for homozygosity -2.0 in a laboratory setting or -1.0 in a database setting.
The case evidence contains no unaffected-person co-occurrence, qualifying second ATM allele, phase, or setting information for c.182T>G/p.Phe61Cys/p.F61C.
The exact-variant search found c.182T>G/F61C in Suppl_TableS1_PMID 40580951, but that row is a functional-table entry and contains no unaffected-person co-occurrence or allelic-phase evidence relevant to BP2.
Still missing
No unaffected non-Ataxia-Telangiectasia adult carrying NM_000051.4:c.182T>G with a pathogenic or likely pathogenic ATM variant was identified.
No trans/cis phase, phase-unknown co-occurrence, laboratory/database setting, or qualifying homozygous observation was documented.
ATM_PM3_BP2_1.5.pdf was searched for c.182T>G, p.Phe61Cys, and p.F61C; no entry for this variant was found.
Sources
vcep_atm_pm3_bp2_1_5
Not applicable · 16· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.182T>G is a missense variant, whereas ATM PVS1 covers null variants such as nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variants.
Details ▾Hide ▴
Reasoning
NM_000051.4:c.182T>G (NP_000042.3:p.(Phe61Cys), p.(F61C)) is a missense substitution in exon 3, not a null variant. The governing ClinGen HBOP ATM VCEP v1.5 PVS1 specification limits PVS1 to nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, and single- or multi-exon deletion variants. Therefore PVS1 is not applicable; no strength tier is assigned. The variant was searched as c.182T>G, p.Phe61Cys, and p.F61C in ATM_PVS1_1.5.pdf, with no variant-specific entry found.
Rule
ATM HBOP VCEP v1.5 PVS1: applicable only to specified null-variant classes; missense variants are outside scope.
Evidence considered
The case normalization identifies NM_000051.4:c.182T>G as NP_000042.3:p.(Phe61Cys)/p.(F61C), with consequence_class missense and canonical_splice_consensus false.
ATM_PVS1_1.5.pdf states that PVS1 is for null variants: nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, and single- or multi-exon deletion variants.
The variant was searched in the governing ATM_PVS1_1.5.pdf using c.182T>G, p.Phe61Cys, and p.F61C; no variant-specific row was found.
Still missing
No variant-specific entry for c.182T>G, p.Phe61Cys, or p.F61C was found in ATM_PVS1_1.5.pdf; this does not alter the missense-based inapplicability of PVS1.
PS2VCEPNot applicable: the ATM Version 1.6 specification explicitly marks PS2 as Not Applicable.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM Version 1.6 specification marks PS2 as Not Applicable. Therefore, generic de novo evidence rules are not used for this ATM variant, regardless of whether parental testing or a de novo observation is available.
VCEP rule
ATM Version 1.6: PS2 = Not Applicable.
Evidence considered
The governing ATM Version 1.6 framework lists PS2 applicability as Not Applicable.
PM1VCEPNot applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants share domains and germline hotspots are not well defined.
Details ▾Hide ▴
Reasoning
The governing ATM VCEP explicitly marks PM1 not applicable because benign and pathogenic variants occur in the same domains and germline mutational hotspots are not well defined. The authoritative vcep_materials.json domain_tables key is present but empty, so there is no approved domain list that can override the VCEP prohibition.
VCEP rule
ATM VCEP PM1: do not use.
Evidence considered
The ATM VCEP framework marks PM1 not applicable and instructs: benign and pathogenic variants are known to occur within the same domains, while germline mutational hotspots are not well defined.
The authoritative vcep_materials.json domain_tables key is present and empty.
PM4N/ANot applicable: p.(Phe61Cys) is a missense substitution, while the ATM VCEP PM4 rule is restricted to stop-loss variants.
Details ▾Hide ▴
Reasoning
The governing ATM VCEP specification defines PM4 for stop-loss variants. NM_000051.4:c.182T>G produces the missense substitution p.(Phe61Cys), not a stop-loss or other protein-length change. PM4 is therefore not applicable.
Rule
ATM HBOP VCEP PM4: use for stop-loss variants.
Evidence considered
The case normalization identifies NM_000051.4:c.182T>G as the missense substitution NP_000042.3:p.(Phe61Cys)/p.(F61C), with no protein-length change.
The ATM VCEP rule for PM4 states: use for stop-loss variants.
PM5N/ANot applicable: ATM PM5 is restricted to qualifying truncating or RNA-supported splice variants and explicitly excludes missense changes such as p.Phe61Cys.
Details ▾Hide ▴
Reasoning
The ATM VCEP PM5 rule is applicable only to specified NMD-prone truncating variants upstream of p.Leu3048, with PVS1 at Very Strong, or qualifying observed RNA-supported splice variants. It explicitly says not to use PM5 for missense changes because different substitutions at one residue may be pathogenic or benign. This variant is missense p.Phe61Cys.
Rule
ATM VCEP PM5: do not use for missense changes; use only the specified truncating or observed RNA-supported splice paths.
Evidence considered
The ATM VCEP PM5 instructions restrict PM5_Supporting to NMD-prone truncating variants upstream of p.Leu3048 with PVS1 Very Strong, or qualifying observed RNA-supported splice variants.
The same VCEP instructions explicitly state not to use PM5 for missense changes.
The variant is an exonic missense substitution, NM_000051.4:c.182T>G, p.Phe61Cys, and the PM5 candidate artifact found no eligible classic missense comparator.
PM6VCEPNot applicable: the ATM Version 1.6 specification explicitly marks PM6 as Not Applicable.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM Version 1.6 specification marks PM6 as Not Applicable. Therefore, generic presumed de novo evidence rules are not used for this ATM variant, even if a presumed de novo report were identified.
VCEP rule
ATM Version 1.6: PM6 = Not Applicable.
Evidence considered
The governing ATM Version 1.6 framework lists PM6 applicability as Not Applicable.
PP2VCEPNot applicable: the ATM VCEP states that ATM lacks a defined low rate of benign missense variation required for PP2.
Details ▾Hide ▴
Reasoning
The ATM VCEP marks PP2 not applicable and instructs not to use it because ATM does not have a defined low rate of benign missense variation. The variant's missense consequence therefore does not qualify it for PP2 under the governing framework.
VCEP rule
ATM VCEP PP2: do not use.
Evidence considered
The ATM VCEP PP2 rule is marked not applicable and states: do not use because ATM does not have a defined low rate of missense benign variation.
PP4VCEPNot applicable: the ATM VCEP excludes PP4 because cancer phenotypes are nonspecific and ataxia-telangiectasia phenotype evidence is incorporated into PM3/BP2.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP version 1.6 marks PP4 as not applicable. For autosomal-dominant ATM-related cancer predisposition, the VCEP states not to use PP4 because breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes; for autosomal-recessive ataxia telangiectasia, phenotype evidence is incorporated into the PM3/BP2 framework rather than used as a separate PP4 line of evidence.
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 version 1.6 marks PP4 "Not applicable" and directs that it not be used separately for either ATM disease context.
PP5VCEPNot applicable: the ATM VCEP excludes PP5, and no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.
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Reasoning
The governing ClinGen HBOP ATM VCEP version 1.6 marks PP5 as not applicable. Independently, the variant has no ClinVar record or exact-variant expert-panel Pathogenic/Likely pathogenic classification in the reviewed evidence, so the required expert-panel trigger for PP5 is absent.
VCEP rule
This criterion is not applicable under the ClinGen HBOP ATM VCEP version 1.6.
Evidence considered
ClinGen HBOP ATM VCEP version 1.6 marks PP5 "Not Applicable".
ClinVar returned no record for NM_000051.4:c.182T>G, so no exact-variant expert-panel Pathogenic or Likely pathogenic assertion can trigger PP5.
BS2VCEPNot applicable: the ATM VCEP excludes BS2 because ATM-related cancer predisposition has incomplete penetrance.
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Reasoning
The ATM VCEP version 1.6 marks BS2 as not applicable because ATM-related cancer predisposition has incomplete penetrance. Therefore, the absence or presence of this variant in healthy adults is not adjudicated with BS2 under the governing specification.
VCEP rule
Do not use: ATM has incomplete penetrance; ATM VCEP v1.6
Evidence considered
ClinGen HBOP ATM VCEP version 1.6 states that BS2 is not applicable because ATM has incomplete penetrance.
BS4VCEPNot applicable: the ATM Version 1.6 specification explicitly marks BS4 as Not Applicable.
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Reasoning
The governing ClinGen HBOP ATM Version 1.6 specification marks BS4 as Not Applicable. Therefore, generic non-segregation evidence rules are not used for this ATM variant, regardless of any unaffected carriers or discordant relatives.
VCEP rule
ATM Version 1.6: BS4 = Not Applicable.
Evidence considered
The governing ATM Version 1.6 framework lists BS4 applicability as Not Applicable.
BP1VCEPNot applicable: the ATM VCEP excludes BP1 because pathogenic missense variants are known for ATM.
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Reasoning
The ATM VCEP marks BP1 not applicable and explicitly instructs not to use it because missense pathogenic variants are known for ATM. This variant is a missense substitution, so the benign criterion is excluded by the governing gene-specific framework.
VCEP rule
ATM VCEP BP1: do not use.
Evidence considered
The ATM VCEP BP1 rule is marked not applicable and states: do not use because missense pathogenic variants are known for ATM.
NM_000051.4:c.182T>G is an exonic missense variant producing p.Phe61Cys.
BP3VCEPNot applicable: ATM VCEP marks BP3 as not applicable, and c.182T>G is a missense substitution rather than an in-frame repeat-region indel.
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Reasoning
The ATM VCEP framework marks BP3 as not applicable. Independently, NM_000051.4:c.182T>G is a missense substitution rather than an in-frame deletion or insertion in a repetitive region, so the repeat-region protein-change criterion does not apply.
VCEP rule
ATM HBOP VCEP BP3: Not Applicable.
Evidence considered
The ATM VCEP framework explicitly lists BP3 as Not Applicable.
The case normalization identifies NM_000051.4:c.182T>G as a missense substitution, not an in-frame deletion or insertion in a repetitive region.
BP5VCEPNot applicable: the governing ATM VCEP marks BP5 as not applicable for this variant assessment.
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Reasoning
The governing ClinGen HBOP ATM VCEP version 1.6 marks BP5 as not applicable. Therefore no BP5 evidence is assigned, and no numeric BP5 threshold is applicable to this variant under the governing framework.
VCEP rule
Not applicable under the ClinGen HBOP ATM VCEP version 1.6.
Evidence considered
ClinGen HBOP ATM VCEP version 1.6 marks BP5 "Not applicable".
BP6VCEPNot applicable: the ATM VCEP excludes BP6, and no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.
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Reasoning
The governing ClinGen HBOP ATM VCEP version 1.6 marks BP6 as not applicable and states that the criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. In addition, no exact-variant ClinVar expert-panel Benign or Likely benign classification is present.
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 version 1.6 marks BP6 "Not Applicable for this VCEP" and says it is not for use.
ClinVar returned no record for NM_000051.4:c.182T>G, so no exact-variant expert-panel Benign or Likely benign assertion can trigger BP6.
BP7N/ANot applicable: c.182T>G produces the missense change p.Phe61Cys, whereas BP7 is restricted to synonymous or qualifying deep-intronic variants.
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Reasoning
BP7 applies only to synonymous or qualifying deep-intronic variants. NM_000051.4:c.182T>G produces the missense substitution p.(Phe61Cys) / p.(F61C), so BP7 is outside its criterion scope and no synonymous-variant assessment is performed.
Rule
ATM VCEP v1.6 BP7 scope: synonymous and qualifying deep-intronic variants only.
Evidence considered
The normalized consequence is missense, NM_000051.4:c.182T>G to NP_000042.3:p.(Phe61Cys) / p.(F61C).
The ATM VCEP v1.6 BP7 rule is scoped to synonymous and qualifying deep-intronic variants, not missense substitutions.
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ATM—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Pangolin splice lossmagnitude shown
-0.444
Pangolin splice gain
0.793
Other predictors
REVEL
0.620
BayesDel
0.219
How the predictions were used
PP3Not met: REVEL 0.62 is below the ATM VCEP PP3 Supporting threshold of >0.7333 for missense variants.
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Reasoning
This is a missense variant, so the ATM VCEP missense REVEL path applies and SpliceAI is not used. The governing ATM VCEP v1.6 specifies PP3 Supporting for REVEL >0.7333. The exact c.182T>G / F61C row in the governing Sun et al. Table S1 reports REVEL 0.62, which is below the VCEP threshold; therefore PP3 is not met. The row's Functional / Medium-high / DeepATM_predicted=No fields are direct functional-screen outputs, not a calibrated PP3 code, and are not used to assign this computational criterion.
The ATM VCEP v1.6 specification assigns PP3 Supporting to missense variants with REVEL >0.7333.
The local REVEL lookup reports a score of 0.62 for NM_000051.4:c.182T>G (p.Phe61Cys/p.F61C).
The exact c.182T>G row in Suppl_TableS1_PMID 40580951 reports F61C, Missense, REVEL 0.62, Classification Functional, Confidence Medium-high, and DeepATM_predicted No; these latter fields are functional-screen results and were not converted into PP3.
BP4Not met: REVEL 0.62 exceeds the ATM VCEP BP4 Supporting threshold of <=0.249 for missense variants.
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Reasoning
This is a missense variant, so BP4 is evaluated only through the ATM VCEP missense REVEL path; the SpliceAI result is not substituted. The governing ATM VCEP v1.6 specifies BP4 Supporting for REVEL <=0.249. The exact c.182T>G / F61C row and the local REVEL lookup both report 0.62, which is above 0.249 and lies in the non-benign gray zone; therefore BP4 is not met. No SpliceAI score is available, but that missing splice result does not alter the missense BP4 conclusion.
The ATM VCEP v1.6 specification assigns BP4 Supporting to missense variants with REVEL <=0.249.
The local REVEL lookup reports a score of 0.62 for NM_000051.4:c.182T>G (p.Phe61Cys/p.F61C), so it does not meet the BP4 cutoff.
The exact c.182T>G row in Suppl_TableS1_PMID 40580951 independently reports REVEL 0.62.
SpliceAI returned no score, which is missing data rather than evidence for BP4; in any event, SpliceAI is not the applicable BP4 path for this missense variant.
BP7N/ANot applicable: c.182T>G produces the missense change p.Phe61Cys, whereas BP7 is restricted to synonymous or qualifying deep-intronic variants.
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Reasoning
BP7 applies only to synonymous or qualifying deep-intronic variants. NM_000051.4:c.182T>G produces the missense substitution p.(Phe61Cys) / p.(F61C), so BP7 is outside its criterion scope and no synonymous-variant assessment is performed.
Rule
ATM VCEP v1.6 BP7 scope: synonymous and qualifying deep-intronic variants only.
Evidence considered
The normalized consequence is missense, NM_000051.4:c.182T>G to NP_000042.3:p.(Phe61Cys) / p.(F61C).
The ATM VCEP v1.6 BP7 rule is scoped to synonymous and qualifying deep-intronic variants, not missense substitutions.
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.62. BayesDel score = 0.219157.
0 paper records listed. 1 cited in the classification.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.62. BayesDel score = 0.219157.
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.
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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