0%
ATMc.7592T>CLikely benign
Print report
Variant interpretation report

ATM c.7592T>C, p.Met2531Thr

NM_000051.4:c.7592T>C NP_000042.3:p.(Met2531Thr) Missense · exon 51 View identifiers
Classification
Likely benign

Variant description:

The ATM NM_000051.4:c.7592T>C (NP_000042.3:p.(Met2531Thr)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Direct prime-editing classified c.7592T>C as Functional with High confidence and DeepATM_predicted=No. Based on available guidelines, this variant is considered to be Likely Benign.

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

Likely benign.A likely benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ATM

ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen ATM VCEP v1.6. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 2
Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 2
BS3Supporting
BS3 · supporting

Met at Supporting: direct prime-editing classified c.7592T>C as Functional with High confidence and DeepATM_predicted=No.

BP4Supporting
BP4 · supporting

Met at Supporting: REVEL 0.196 is below the VCEP BP4 missense cutoff of <=.249.

Recorded classification: Likely benign

Likely Benign: BS3 (supporting) and BP4 (supporting) satisfy the ATM VCEP Version 1.6 Rule19 requirement for at least two supporting benign criteria.

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
79 / 1,613,264 alleles

gnomAD v4.1: 79 / 1,613,264 alleles. Recorded AF 4.8969e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.24857e-05; MAF= 0.00425%, 12/282448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29786e-05; MAF= 0.00930%, 12/129062 alleles, homozygotes = 0); grpmax FAF= 5.38e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010857763300760044, 2/18420 alleles, homozygotes = 0).

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

Recorded REVEL score: 0.196. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
ClinVar submissions
13 reported laboratory submissions

11 Uncertain significance · 2 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

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

Applied · BS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 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.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is not applicable because the variant is a missense SNV, outside the ATM VCEP's specified null-variant PVS1 classes.

PM4 is not applicable because the variant is not stop-loss.

BP3 is not applicable under the ATM VCEP CSPEC.

Only PS4, PP4, PP5, BP5, and BP6 were adjudicated.

PS4 remains not_assessed because the available case-control evidence is gene-level or missense-class-level rather than variant-specific and lacks the VCEP-required variant-specific p-value and effect estimate/95% confidence interval.

PP4, PP5, BP5, and BP6 are not_applicable under the ATM VCEP's explicit instructions.

Computational evidence was adjudicated from the VCEP's own missense and splicing paths without double-counting REVEL or SpliceAI across criteria.

The exact VCEP-governing Table S1 row was found for c.7592T>C / M2531T; it reports REVEL 0.196, Classification=Functional, Confidence=High, and DeepATM_predicted=No.

Met · 2

BS3 SupportingVCEPMet at Supporting: direct prime-editing classified c.7592T>C as Functional with High confidence and DeepATM_predicted=No. Details ▾Hide ▴
Reasoning

The exact ATM VCEP Table S1 row for NM_000051.4:c.7592T>C (p.Met2531Thr/p.M2531T) reports Classification=Functional, Confidence=High, and DeepATM_predicted=No. The file-specific rule states that DeepATM_predicted=No with a high-confidence Functional classification is a direct prime-editing measurement that supports BS3_Supporting. No conflicting exact-variant result was found in the approved-assay calibration file, which was searched under all three requested variant notations.

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.7592T>C / M2531T: Classification=Functional, Confidence=High, DeepATM_predicted=No; the VCEP file-specific rule assigns BS3_Supporting to this direct prime-editing result.
  • The ATM VCEP CSPEC BS3 Supporting rule is satisfied by functional rescue of either an ATM-specific feature or radiosensitivity; the exact row's Functional direct assay result supports the benign functional direction, while no stronger-than-Supporting code is assigned from this file.
  • ClinGen HBOP ATM Supplementary Tables 1 and 2 were searched for c.7592T>C, p.Met2531Thr, and p.M2531T; no exact-variant notation was found.
Still missing
  • No c.7592T>C, p.Met2531Thr, or p.M2531T entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; the file provides assay calibration, not variant-specific results.
  • The approved assay calibration file's cited papers were not established as having tested this exact variant.
Sources
vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
BP4 SupportingVCEPMet at Supporting: REVEL 0.196 is below the VCEP BP4 missense cutoff of <=.249. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and the VCEP BP4 missense path requires REVEL score <=.249. The exact REVEL score is 0.196, so BP4 Supporting is met. SpliceAI also shows no predicted splice impact (max delta 0.004, <=0.1), but this is not counted as a second BP4 path or additional strength; the missense REVEL path is sufficient. The exact VCEP Table S1 row independently reports REVEL 0.196 and Functional, High-confidence, DeepATM_predicted=No.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • Local REVEL lookup for NM_000051.4:c.7592T>C / NP_000042.3:p.(M2531T): REVEL score 0.196, satisfying the VCEP missense BP4 cutoff.
  • SpliceAI lookup: max delta score 0.004, which is <=0.1, but the splice result is not independently added to BP4 for this missense variant.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7592T>C / M2531T: REVEL 0.196; Classification=Functional; Confidence=High; DeepATM_predicted=No.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Not met · 5 · evaluated, threshold not reached

PS3 VCEPNot met: direct prime-editing classified c.7592T>C as Functional with High confidence, not as a variant that fails to rescue ATM function. Details ▾Hide ▴
Reasoning

The exact ATM VCEP Table S1 row for NM_000051.4:c.7592T>C (p.Met2531Thr/p.M2531T) reports Classification=Functional, Confidence=High, and DeepATM_predicted=No, indicating a direct prime-editing measurement with functional rather than non-functional activity. Under the VCEP PS3 rule, this does not support a failed rescue. The approved ATM assay calibration file was also searched for c.7592T>C, p.Met2531Thr, and p.M2531T; no variant-specific entry was found there, and that file is methodological rather than a per-variant results table.

VCEP rule
Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency
Evidence considered
  • Sun et al. 2025 Supplementary Table S1, exact row c.7592T>C / M2531T: Combined_score=-0.717357124110041, Classification=Functional, Confidence=High, DeepATM_predicted=No; this is a direct prime-editing measurement under the file's PS3/BS3 curation policy.
  • ClinGen HBOP ATM VCEP Supplementary Tables 1 and 2 were searched for c.7592T>C, p.Met2531Thr, and p.M2531T; no exact-variant notation was found. The file's approved assay methods cannot independently establish PS3 for this variant without confirmation in one of its cited papers.
Still missing
  • No c.7592T>C, p.Met2531Thr, or p.M2531T entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; the file provides assay calibration, not variant-specific results.
  • No exact-variant result was established from the three approved assay papers cited by the calibration file (PMID:18634022, PMID:19431188, or PMID:11805335).
Sources
vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
PM2 VCEPNot met: the highest gnomAD v4.1 subpopulation frequency is 0.00644213%, exceeding the VCEP PM2 threshold of <=0.001%. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PM2 Supporting when the frequency is <=0.001% in the gnomAD subpopulation with the highest frequency, with an exception only when frequency is >0.001% but n=1 in a single subpopulation and absent from all others. The highest all-comers subpopulation frequency is 6.44213e-05 (0.00644213%) in gnomAD v4.1 European non-Finnish, based on 76/1,179,734 alleles, and the variant is present in multiple populations; thus PM2 is not met. The gnomAD v2.1 highest subpopulation frequency is 9.29786e-05 (0.00929786%) in European non-Finnish, based on 12/129,062 alleles.

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 <=0.001% in gnomAD subpopulation with the highest frequency; the n=1 single-subpopulation exception does not apply here.
  • gnomAD v4.1 all-comers: European non-Finnish is the highest-frequency subpopulation at 6.44213e-05 (0.00644213%), 76/1,179,734 alleles, 0 homozygotes; the total dataset has 79/1,613,264 alleles and 0 homozygotes.
  • gnomAD v2.1 all-comers: European non-Finnish is the highest-frequency subpopulation at 9.29786e-05 (0.00929786%), 12/129,062 alleles, 0 homozygotes; the total dataset has 12/282,448 alleles and 0 homozygotes.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
PP3 VCEPNot met: REVEL 0.196 is below the VCEP PP3 missense threshold of >.7333, and SpliceAI max delta 0.004 is below its >=0.2 splice threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the VCEP PP3 missense path requires REVEL >.7333; the exact REVEL score is 0.196, below that threshold. The VCEP also permits a splicing path for missense/in-frame variants outside donor and acceptor 1,2 sites when SpliceAI >=0.2; SpliceAI max delta is 0.004, also below threshold. The governing VCEP table row is an exact match (c.7592T>C / M2531T) and reports REVEL 0.196; its Functional, High-confidence, DeepATM_predicted=No result is functional-table corroboration and is not used as a computational PP3 code.

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
  • Local REVEL lookup for NM_000051.4:c.7592T>C / NP_000042.3:p.(M2531T): REVEL score 0.196.
  • SpliceAI lookup for NM_000051.4:c.7592T>C: DS_AG 0.003, DS_AL 0.004, DS_DG 0.000, DS_DL 0.001; max delta score 0.004.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7592T>C / M2531T: REVEL 0.196; Classification=Functional; Confidence=High; DeepATM_predicted=No. The table's predictor values are used as corroboration only for this computational assessment.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax FAF is 0.005276%, below the VCEP BA1 threshold of >0.5%. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BA1 as Grpmax Filtering AF >0.5% in gnomAD. The all-comers gnomAD v4.1 grpmax FAF is 5.276e-05 (0.005276%), which is below 0.5%; therefore BA1 is not met. The gnomAD v2.1 grpmax FAF is likewise below the threshold at 5.38e-05.

VCEP rule
Grpmax Filtering AF **>.5%** in gnomAD
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BA1 rule: Grpmax Filtering AF >0.5% in gnomAD.
  • gnomAD v4.1 all-comers: grpmax FAF 5.276e-05 (0.005276%), with 79/1,613,264 total alleles and 0 homozygotes.
  • gnomAD v2.1 all-comers: grpmax FAF 5.38e-05 (0.00538%), with 12/282,448 total alleles and 0 homozygotes.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax FAF is 0.005276%, below the VCEP BS1 threshold of >0.05%. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BS1 as Grpmax Filtering AF >0.05% in gnomAD. The all-comers gnomAD v4.1 grpmax FAF is 5.276e-05 (0.005276%), below 0.05%; therefore BS1 is not met. The gnomAD v2.1 grpmax FAF is also below the threshold at 5.38e-05.

VCEP rule
Grpmax Filtering AF **>.05%** in gnomAD
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BS1 rule: Grpmax Filtering AF >0.05% in gnomAD.
  • gnomAD v4.1 all-comers: grpmax FAF 5.276e-05 (0.005276%), with 79/1,613,264 total alleles and 0 homozygotes.
  • gnomAD v2.1 all-comers: grpmax FAF 5.38e-05 (0.00538%), with 12/282,448 total alleles and 0 homozygotes.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗

Not assessed · 5 · no assessment recorded

PS1 VCEPNot assessed: no same-amino-acid established pathogenic comparator and no qualifying evidence ruling out splicing for both missense alterations. Details ▾Hide ▴
Reasoning

The ATM VCEP PS1 rule requires the same amino-acid change as a previously established pathogenic variant and, for missense changes, requires a splice defect to be ruled out for both alterations by RNA analysis and/or in-silico splice predictions. The case evidence does not identify a previously established pathogenic comparator with the same amino-acid change, and the governing ATM_PS1_1.6.pdf splicing table contains no entry for c.7592T>C, p.Met2531Thr, or p.M2531T after all three notations were searched. Therefore PS1 cannot be assessed from the available VCEP-governed evidence.

VCEP rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change • Missense: This rule may be applied only when a splice defect is ruled out for both alterations either by RNA analysis and/or in silico splice predictions
Evidence considered
  • ATM VCEP v1.6 PS1 rule: PS1 is for the same amino-acid change as a previously established pathogenic variant; missense use requires a splice defect to be ruled out for both alterations by RNA analysis and/or in-silico splice predictions.
  • ATM_PS1_1.6.pdf, PS1 splicing table: searches for c.7592T>C, p.Met2531Thr, and p.M2531T returned no matching entry.
  • Case normalization: NM_000051.4:c.7592T>C encodes NP_000042.3:p.(Met2531Thr) / p.(M2531T).
Still missing
  • A previously established pathogenic ATM variant with the same p.Met2531Thr amino-acid change was not identified in the available evidence.
  • ATM_PS1_1.6.pdf was searched for c.7592T>C, p.Met2531Thr, and p.M2531T; no entry for this variant was found.
  • Qualifying RNA or in-silico splice evidence for both the target and a same-amino-acid pathogenic comparator is unavailable.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗
PS4 VCEPNot assessed: the available case-control paper reports ATM missense classes, not this variant, so variant-specific p-value, effect estimate, and 95% confidence interval are unavailable. Details ▾Hide ▴
Reasoning

The ATM VCEP makes PS4 applicable and requires a case-control study with p-value <=.05 and either an odds ratio, hazard ratio, or relative risk >=2 or a lower 95% CI >=1.5. The reviewed literature contains gene-level ATM case-control evidence in PMID:19781682 (1544 breast-cancer cases and 1224 controls from seven studies, plus 987 cases and 1021 controls), but the paper does not mention NM_000051.4:c.7592T>C or p.(M2531T) and provides no variant-specific case and control counts, p-value, effect estimate, or confidence interval. Therefore the VCEP PS4 inequality cannot be evaluated for this variant; no OR or 95% CI was computed because the required variant-specific counts are unavailable.

VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥2 **or** lower 95% CI ≥1.5).
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PS4 rule: case-control studies require p-value <=.05 and (odds ratio, hazard ratio, or relative risk >=2 or lower 95% CI >=1.5).
  • Tavtigian et al. (PMID:19781682), Abstract: pooled ATM case-control analysis included 1544 breast-cancer cases and 1224 controls from seven published studies plus 987 additional cases and 1021 controls, but the exact ATM c.7592T>C/p.M2531T variant was not mentioned and variant-specific counts were not reported.
  • The literature_pass packet has no ai_classified_papers; the reviewed paper-extract evidence likewise contains no exact-variant case-control result.
Still missing
  • Variant-specific affected-case and unaffected/control counts, or a directly reported variant-specific p-value and effect estimate with 95% confidence interval, are needed to evaluate PS4.
Sources
cspec ↗PMID:19781682 ↗PMID:20301425 ↗
PM3 VCEPNot assessed: no affected A-T proband, second allele, or phase information is available to assign the VCEP's PM3 points. Details ▾Hide ▴
Reasoning

The ATM VCEP PM3/BP2 table assigns PM3 points only from unrelated A-T probands according to phenotype confidence and whether the variant under assessment is confirmed in trans, phase-unknown, paired with an unidentified/VUS second variant, or homozygous. The available case evidence contains no affected A-T proband observation, second-allele identity, phase result, or inheritance data for NM_000051.4:c.7592T>C (p.Met2531Thr/p.M2531T), so no PM3 points or strength can be assigned. The governing file ATM_PM3_BP2_1.6.pdf was searched for c.7592T>C, p.Met2531Thr, and p.M2531T; no variant-specific entry was found.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant; assign PM3 strength from the ATM PM3/BP2 points table.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, PM3 section and Ataxia Telangiectasia PM3/BP2 table: PM3 uses points per unrelated A-T proband, with 4.0/2.0 points for a confident phenotype when confirmed in trans/phase unknown, and lower values for other zygosity or phenotype categories.
  • The governing ATM_PM3_BP2_1.6.pdf file was searched under c.7592T>C, p.Met2531Thr, and p.M2531T; no matching variant-specific row was found.
  • Case evidence for NM_000051.4:c.7592T>C identifies a missense variant but provides no A-T proband, affected-proband phenotype classification, second ATM allele, or phase information.
Still missing
  • No variant-specific entry for c.7592T>C, p.Met2531Thr, or p.M2531T was found in ATM_PM3_BP2_1.6.pdf.
  • Affected A-T proband observations and phenotype confidence are unavailable.
  • The second ATM allele and its pathogenicity classification are unavailable.
  • Phase or parental genotyping confirming the variant in trans is unavailable.
Sources
vcep_atm_pm3_bp2_1_6 ↗
PP1 VCEPNot assessed: no affected-relative segregation or parental-phase result is documented, so the VCEP's 1-, 2-, or ≥3-relative PP1 thresholds cannot be evaluated. Details ▾Hide ▴
Reasoning

PP1 is applicable only on the ATM VCEP's autosomal-recessive segregation path, with supporting strength for segregation in 1 affected relative, moderate strength for 2, and strong strength for at least 3. The available case evidence provides no documented affected relative, parental testing, phase, meiosis, or family segregation result for NM_000051.4:c.7592T>C, so no PP1 strength can be assigned. The available segregation-themed publication reports other ATM variants and does not mention this variant.

VCEP rule
* AR Condition: Affected relatives must have both variants identified in proband. * AD Condition – Do not use: Co-segregation analysis in lower-penetrance genes can lead to false positive results (PMID 32773770)...AR Condition: Segregation in ≥3 affected relatives...AR Condition: Segregation in 2 affected relatives...AR Condition: Segregation in 1 affected relative
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PP1: AR segregation in 1 affected relative is supporting, 2 affected relatives is moderate, and ≥3 affected relatives is strong; the AD path is explicitly not to be used.
  • The case evidence contains no variant-specific affected-relative segregation count, parental testing result, phase result, or informative meiosis for NM_000051.4:c.7592T>C.
  • The segregation-themed paper indexed as PMID:28726808 reports eight ATM pathogenic-variant carriers in a pancreatic-cancer cohort, but the listed ATM variants do not include c.7592T>C and the paper provides no usable segregation result for this variant.
Still missing
  • Documented testing and phenotype status for affected relatives
  • Parental or offspring testing establishing phase and informative meioses
  • Variant-specific family segregation data for NM_000051.4:c.7592T>C
Sources
cspec ↗PMID:28726808 ↗
BP2 VCEPNot assessed: no unaffected adult, pathogenic co-occurring variant, or cis/trans phase observation is available for the VCEP's BP2 points assignment. Details ▾Hide ▴
Reasoning

The ATM VCEP BP2 rule concerns an observation in trans with a pathogenic variant in a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern; its ATM table assigns negative points for unaffected non-A-T adults with a pathogenic or likely pathogenic variant in trans or with unknown phase. The available case evidence contains no unaffected adult proband, pathogenic co-occurring variant, phase result, or cis observation for NM_000051.4:c.7592T>C (p.Met2531Thr/p.M2531T), so BP2 cannot be assigned. The governing file ATM_PM3_BP2_1.6.pdf was searched for c.7592T>C, p.Met2531Thr, and p.M2531T; no variant-specific entry was found.

VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, BP2 section and Ataxia Telangiectasia PM3/BP2 table: BP2 applies to the specified cis/trans observations and assigns -4.0 points for confirmed in trans, -2.0 for phase unknown, or -2.0/-1.0 for homozygous observations in laboratory/database settings.
  • The governing ATM_PM3_BP2_1.6.pdf file was searched under c.7592T>C, p.Met2531Thr, and p.M2531T; no matching variant-specific row was found.
  • Case evidence for NM_000051.4:c.7592T>C contains no unaffected adult observation, co-occurring pathogenic ATM variant, or cis/trans phase result.
Still missing
  • No variant-specific entry for c.7592T>C, p.Met2531Thr, or p.M2531T was found in ATM_PM3_BP2_1.6.pdf.
  • An unaffected non-A-T adult proband observation is unavailable.
  • A co-occurring pathogenic or likely pathogenic variant is not documented.
  • Phase information establishing cis or trans is unavailable.
Sources
vcep_atm_pm3_bp2_1_6 ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.7592T>C is a missense SNV in exon 51, whereas the ATM VCEP PVS1 rule applies to specified null variants rather than ordinary missense substitutions. Details ▾Hide ▴
Reasoning

NM_000051.4:c.7592T>C (NP_000042.3:p.(Met2531Thr), p.M2531T) is a missense SNV in exon 51, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. The ATM VCEP PVS1 rule is restricted to null variants and its decision tree does not provide a PVS1 path for an ordinary missense substitution; therefore PVS1 is not applicable. The search of ATM_PVS1_1.6.pdf.txt for c.7592T>C, p.Met2531Thr, and p.M2531T found no variant-specific entry.

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease ... PVS1 can be applied as per the below decision tree.
Evidence considered
  • Variant facts: NM_000051.4:c.7592T>C; NP_000042.3:p.(Met2531Thr) / p.(M2531T); exon 51; missense consequence; canonical splice consensus false.
  • ATM_PVS1_1.6.pdf, PVS1 definition and ATM PVS1/PVS1(RNA) Guide: the VCEP defines PVS1 for null variants and provides its decision tree for those variant classes.
  • ATM_PVS1_1.6.pdf.txt was searched for c.7592T>C, p.Met2531Thr, and p.M2531T; no exact variant-specific entry was found.
Still missing
  • ATM_PVS1_1.6.pdf.txt: no entry found for c.7592T>C, p.Met2531Thr, or p.M2531T; the result therefore uses the governing general rule rather than a pre-assigned variant-specific code.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗
PS2 VCEPNot applicable: the ATM VCEP excludes PS2 for autosomal-dominant and autosomal-recessive disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PS2 not applicable and instructs that it should not be used for either autosomal-dominant or autosomal-recessive disease because informative de novo occurrences have not been observed and de novo autosomal-recessive conditions are unlikely to be informed by phase.

VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PS2: marked not applicable with an explicit instruction not to use for AD or AR disease.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP v1.6 explicitly marks PM1 as Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC marks PM1 as Not Applicable. The case vcep_materials.json domain_tables object has no ATM entry, but no independently derived domain route may be substituted for the VCEP applicability designation.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC criteria entry for PM1: applicability is "Not Applicable".
  • vcep_materials.json domain_tables: no ATM entry is present.
Sources
cspec ↗
PM4 N/ANot applicable: p.(Met2531Thr) is a missense substitution, not a stop-loss variant, so it does not meet the ATM VCEP PM4 applicability rule. Details ▾Hide ▴
Reasoning

The ATM VCEP specifies PM4 for stop-loss variants. This variant is c.7592T>C, p.(Met2531Thr), a missense SNV that does not alter a termination codon or produce a protein-length extension; PM4 is therefore not applicable.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • Variant facts: NM_000051.4:c.7592T>C; NP_000042.3:p.(Met2531Thr) / p.(M2531T); missense SNV.
  • ATM VCEP CSPEC PM4 entry: PM4 is specified for stop-loss variants.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 is restricted to qualifying NMD-prone truncating variants upstream of p.Leu3048, whereas this is missense p.Met2531Thr. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 PM5 rule is limited to NMD-prone truncating DNA or observed NMD-prone truncating splice variants receiving PVS1 or PVS1(RNA) at Very Strong with premature termination codons upstream of p.Leu3048. This variant is a missense substitution, c.7592T>C p.Met2531Thr, so the VCEP PM5 rule does not apply.

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 variants must be NMD-prone truncating variants receiving PVS1 at Very Strong with premature termination codons upstream of p.Leu3048; the splice path is likewise limited to observed NMD-prone truncating variants receiving PVS1(RNA) at Very Strong.
  • Case variant consequence: c.7592T>C is a missense SNV encoding p.Met2531Thr.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP excludes PM6 for autosomal-dominant and autosomal-recessive disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PM6 not applicable and instructs that it should not be used for either autosomal-dominant or autosomal-recessive disease because informative de novo occurrences have not been observed and de novo autosomal-recessive conditions are unlikely to be informed by phase.

VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PM6: marked not applicable with an explicit instruction not to use for AD or AR disease.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP v1.6 explicitly marks PP2 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC marks PP2 as Not Applicable. No generic ACMG/AMP PP2 rule or gene-level missense mechanism may be substituted.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC criteria entry for PP2: applicability is "Not Applicable".
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for breast cancer and prohibits separate PP4 use for ataxia-telangiectasia. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly excludes PP4 for both relevant disease contexts: it says not to use PP4 for autosomal-dominant breast cancer because of genetic heterogeneity and lack of distinguishing features, and not to use it as separate 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 v1.6 PP4 instructions: autosomal-dominant breast cancer is genetically heterogeneous without readily distinguishing features, and autosomal-recessive phenotype evidence is built into the PM3/BP2 table.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP prohibits PP5 regardless of reputational-source classifications. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Published or ClinVar pathogenic classifications therefore cannot generate PP5 under this governing framework.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ATM VCEP v1.6 PP5 instructions explicitly prohibit use of PP5.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP prohibits BS2 because ATM has incomplete penetrance. Details ▾Hide ▴
Reasoning

The ATM VCEP states that BS2 should not be used because ATM has incomplete penetrance. BS2 is therefore not applicable regardless of the observed absence of homozygotes in the available gnomAD datasets.

VCEP rule
Do not use: ATM has incomplete penetrance.
Evidence considered
  • ClinGen ATM VCEP v1.6 CSPEC BS2 applicability instruction: Do not use because ATM has incomplete penetrance.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP assigns no BS4 weight because informative lack-of-segregation instances in ataxia-telangiectasia families are too rare. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS4 not applicable. It states that informative lack-of-segregation instances in ataxia-telangiectasia families are too rare to receive weight at this time, and that biallelic unaffected patients may instead be considered under BP2.

VCEP rule
AD Condition: Co-segregation analysis in low penetrance genes can lead to false positive results (PMID 32773770) 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
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for BS4: marked not applicable and excludes weight for informative lack of co-segregation in A-T families.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP v1.6 explicitly marks BP1 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC marks BP1 as Not Applicable. No generic ACMG/AMP BP1 rule may be substituted.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC criteria entry for BP1: applicability is "Not Applicable".
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP marks BP3 not applicable, and c.7592T>C is a missense SNV rather than an in-frame indel in a repetitive region. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC marks BP3 as Not Applicable. Independently, this variant is a missense SNV, not an in-frame deletion or insertion in a repetitive region, so the VCEP does not permit BP3 for this case.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC BP3 entry: applicability is Not Applicable.
  • Variant facts: NM_000051.4:c.7592T>C is a missense SNV producing p.(Met2531Thr), not an in-frame insertion or deletion.
Sources
cspec ↗
BP5 VCEPNot applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants can occur without a distinct phenotype and ATM has low penetrance. Details ▾Hide ▴
Reasoning

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

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
  • ATM VCEP v1.6 BP5 instructions explicitly say not to use BP5 for this framework.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP prohibits BP6 regardless of reputable-source benign classifications. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Benign classifications from reputable sources therefore cannot generate BP6 under this governing framework.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ATM VCEP v1.6 BP6 instructions explicitly prohibit use of BP6.
Sources
cspec ↗
BP7 N/ANot applicable: c.7592T>C is an exonic missense variant, whereas the VCEP BP7 scope is synonymous or deep intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous and deep intronic variants, including the stated RNA path for silent substitutions and intronic variants. NM_000051.4:c.7592T>C is an exonic missense variant producing p.(Met2531Thr), so it lies outside BP7 scope and no BP7 evidence is evaluated.

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
  • Variant normalization identifies NM_000051.4:c.7592T>C as NP_000042.3:p.(Met2531Thr), an exonic missense substitution.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.7592T>C
Protein (HGVS p.)
NP_000042.3:p.(Met2531Thr)
GRCh38
chr11:108331520 T>C
GRCh37
chr11:108202247 T>C
Location and type
Exon 51 · missense
ClinVar
140910

Gene diagram

Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.4. Select a row to find it on the plot.

ATMNM_000051.4
Fetching transcript structure from UCSC…
gnomAD v4.1 79 / 1,613,264 alleles AF 4.9e-05 · 0 homozygotes · FAF 5.28e-05
gnomAD v2.1 12 / 282,448 alleles AF 4.25e-05 · 0 homozygotes · FAF 5.38e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 4.9e-05 · 79 / 1,613,264 alleles · 0 hom · FAF 5.3e-05
European (non-Finnish)76 / 1,179,734 6.4e-05
Remaining individuals3 / 62,462 4.8e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 4.2e-05 · 12 / 282,448 alleles · 0 hom · FAF 5.4e-05
European (non-Finnish)12 / 129,062 9.3e-05
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.8969e-05; MAF= 0.00490%, 79/1613264 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.44213e-05; MAF= 0.00644%, 76/1179734 alleles, homozygotes = 0); grpmax FAF= 5.276e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.24857e-05; MAF= 0.00425%, 12/282448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29786e-05; MAF= 0.00930%, 12/129062 alleles, homozygotes = 0); grpmax FAF= 5.38e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010857763300760044, 2/18420 alleles, homozygotes = 0).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +345 bp
0.004
SpliceAI acceptor gainat -14 bp
0.003
SpliceAI donor lossat +457 bp
0.001
SpliceAI donor gainat -204 bp
0.000
Pangolin splice lossmagnitude shown
-0.006
Pangolin splice gain
0.008

Other predictors

REVEL
0.196
BayesDel
-0.299

How the predictions were used

BP4 SupportingVCEPMet at Supporting: REVEL 0.196 is below the VCEP BP4 missense cutoff of <=.249. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and the VCEP BP4 missense path requires REVEL score <=.249. The exact REVEL score is 0.196, so BP4 Supporting is met. SpliceAI also shows no predicted splice impact (max delta 0.004, <=0.1), but this is not counted as a second BP4 path or additional strength; the missense REVEL path is sufficient. The exact VCEP Table S1 row independently reports REVEL 0.196 and Functional, High-confidence, DeepATM_predicted=No.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • Local REVEL lookup for NM_000051.4:c.7592T>C / NP_000042.3:p.(M2531T): REVEL score 0.196, satisfying the VCEP missense BP4 cutoff.
  • SpliceAI lookup: max delta score 0.004, which is <=0.1, but the splice result is not independently added to BP4 for this missense variant.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7592T>C / M2531T: REVEL 0.196; Classification=Functional; Confidence=High; DeepATM_predicted=No.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP3 VCEPNot met: REVEL 0.196 is below the VCEP PP3 missense threshold of >.7333, and SpliceAI max delta 0.004 is below its >=0.2 splice threshold. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the VCEP PP3 missense path requires REVEL >.7333; the exact REVEL score is 0.196, below that threshold. The VCEP also permits a splicing path for missense/in-frame variants outside donor and acceptor 1,2 sites when SpliceAI >=0.2; SpliceAI max delta is 0.004, also below threshold. The governing VCEP table row is an exact match (c.7592T>C / M2531T) and reports REVEL 0.196; its Functional, High-confidence, DeepATM_predicted=No result is functional-table corroboration and is not used as a computational PP3 code.

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
  • Local REVEL lookup for NM_000051.4:c.7592T>C / NP_000042.3:p.(M2531T): REVEL score 0.196.
  • SpliceAI lookup for NM_000051.4:c.7592T>C: DS_AG 0.003, DS_AL 0.004, DS_DG 0.000, DS_DL 0.001; max delta score 0.004.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7592T>C / M2531T: REVEL 0.196; Classification=Functional; Confidence=High; DeepATM_predicted=No. The table's predictor values are used as corroboration only for this computational assessment.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 N/ANot applicable: c.7592T>C is an exonic missense variant, whereas the VCEP BP7 scope is synonymous or deep intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the VCEP to synonymous and deep intronic variants, including the stated RNA path for silent substitutions and intronic variants. NM_000051.4:c.7592T>C is an exonic missense variant producing p.(Met2531Thr), so it lies outside BP7 scope and no BP7 evidence is evaluated.

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
  • Variant normalization identifies NM_000051.4:c.7592T>C as NP_000042.3:p.(Met2531Thr), an exonic missense substitution.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.196. BayesDel score = -0.2994.

10 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Sun et al. 2025
    Sun et al. 2025 Supplementary Table S1 contains the exact ATM variant row c.7592T>C / M2531T and reports REVEL 0.196, Classification Functional, Confidence High, and DeepATM_predicted No. The REVEL value corroborates the computational PP3/BP4 assessment; the functional classification is not independently converted into PP3 or BP4.
    → BP4 · supporting Names this variant
    PMID 40580951 ↗
    Source detail
    108331520 T C c.7592T>C M2531T exon_51 11 Missense 2531 21 0.1854147 0.127308248158802 0.196 0.1093 4.896904660365e-05 Conflicting classifications of pathogenicity -0.717357124110041 Functional High No

    Location Supplementary Table S1, exact row c.7592T>C / M2531T (converted full-text line 24262)

    Context Table S1 from Sun et al. 2025 covers ATM SNVs using prime-editing functional assessment and DeepATM computational prediction; this exact row is marked Functional, High, DeepATM_predicted No.

Other recorded publications

  • Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.
    Tavtigian SV et al. · 2009
    The paper reports pooled ATM mutation-screening data from breast-cancer cases and controls and finds stronger evidence for increased risk from a subset of rare, evolutionarily unlikely ATM missense substitutions. It does not mention ATM c.7592T>C or p.(M2531T), so it does not provide variant-specific PS4 counts or an evaluable effect estimate for this case.
    Does not name this variant
    PMID 19781682 ↗
    Quoted passage
    There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk.

    Abstract

  • Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.
    Bernstein JL et al. · 2010
    No paper-specific finding is recorded.
    PMID 20305132 ↗
  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    No paper-specific finding is recorded.
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer.
    Pearlman R et al. · 2017
    The paper reports ATM mutations in patients with early-onset colorectal cancer, including 3 ATM-mutated patients and 1 patient with ATM and CHEK2 mutations, but does not mention c.7592T>C or p.(M2531T). It provides no exact-variant phenotype-prevalence or case-control evidence.
    Does not name this variant
    PMID 27978560 ↗
    Quoted passage
    13 had mutations in high- or moderate-penetrance genes not traditionally associated with CRC risk (3, ATM; 1, ATM/CHEK2; 2, BRCA1; 4, BRCA2; 1, CDKN2A; 2, PALB2).

    Results, Germline Results for Patients With MMR-Proficient Tumors

  • Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history.
    Chaffee KG et al. · 2018
    The study reports eight individuals with pathogenic ATM variants among 302 pancreatic ductal adenocarcinoma patients with a positive family history, but the target variant NM_000051.4:c.7592T>C is not among the listed ATM variants and no variant-specific segregation result for it is reported.
    Does not name this variant
    PMID 28726808 ↗
    Quoted passage
    Eight individuals were identified as carrying a PV in ATM, six of whom were FPC.

    Results, Table 2, Table 3, and Discussion paragraph beginning "After BRCA2, ATM was the most common breast cancer risk gene..."

  • Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.
    No paper-specific finding is recorded.
    PMID 34326862 ↗
  • BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.
    No paper-specific finding is recorded.
    PMID 20301425 ↗
  • EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
    No paper-specific finding is recorded.
    PMID 20050888 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

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

gnomAD v4.1 79 / 1,613,264 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.004 Open source ↗
ClinVar 11 Uncertain significance · 2 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.8969e-05; MAF= 0.00490%, 79/1613264 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.44213e-05; MAF= 0.00644%, 76/1179734 alleles, homozygotes = 0); grpmax FAF= 5.276e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.24857e-05; MAF= 0.00425%, 12/282448 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.29786e-05; MAF= 0.00930%, 12/129062 alleles, homozygotes = 0); grpmax FAF= 5.38e-05.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.00010857763300760044, 2/18420 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Likely benign (2 clinical laboratories). (ClinVarID = 140910)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.196. BayesDel score = -0.2994.

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.