0%
ATMc.4424A>CLikely benign
Print report
Variant interpretation report

ATM c.4424A>C, p.Tyr1475Ser

NM_000051.4:c.4424A>C NP_000042.3:p.(Tyr1475Ser) Missense · exon 29 View identifiers
Classification
Likely benign

Variant description:

The ATM NM_000051.4:c.4424A>C (NP_000042.3:p.(Tyr1475Ser)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Direct prime-editing classified c.4424A>C as Functional with Medium-high confidence and DeepATM_predicted=No, satisfying the VCEP BS3 mapping. 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: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP's ≤0.001% highest-subpopulation-frequency threshold.

Benign criteria applied · 2
BS3Supporting
BS3 · supporting

Met at Supporting: direct prime-editing classified c.4424A>C as Functional with Medium-high confidence and DeepATM_predicted=No, satisfying the VCEP BS3 mapping.

BP4Supporting
BP4 · supporting

Met at Supporting: SpliceAI max delta 0.005 is ≤0.1 for the VCEP's no-predicted-splice-impact BP4 path, despite REVEL 0.284.

Recorded classification: Likely benign

Likely Benign: BS3 (supporting) plus BP4 (supporting) satisfy the ATM VCEP's Rule19; PM2 supporting alone does not satisfy a pathogenic rule.

02The sources

Evidence at a glance

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

No screenshot for this evidence
REVEL score
0.284 recorded score

Recorded REVEL score: 0.284. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 →
No screenshot for this evidence
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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: 3 met · 4 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

Only the five requested criteria were adjudicated under the ClinGen HBOP ATM VCEP v1.6; PS4 is not assessed because no case-control evidence is available, while PP4, PP5, BP5, and BP6 are explicitly not applicable in the CSPEC.

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

BP4 is met at Supporting strength through the VCEP's independent splicing path: SpliceAI maximum delta 0.005 is ≤0.1; BP7 is not applicable to this missense variant.

Population evidence supports PM2 at Supporting strength; BA1 and BS1 are not met; BS2 is not applicable under the ATM VCEP.

The governing ATM VCEP text does not specify a non-cancer or exome-only source for these criteria, so the default all-comers gnomAD results were used while recording the available non-cancer results as corroboration.

Met · 3

PM2 SupportingVCEPMet at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the VCEP's ≤0.001% highest-subpopulation-frequency threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PM2 at Supporting strength when the frequency is ≤0.001% in the gnomAD subpopulation with the highest frequency. The variant is absent from gnomAD v2.1 and gnomAD v4.1, and is also absent from the available gnomAD v2.1 non-cancer and v3.1 non-cancer results, so the highest observed frequency is compatible with the VCEP's PM2 Supporting threshold. The VCEP does not require a non-cancer or exome-only subset for PM2; the default all-comers sources were therefore used.

VCEP rule
Frequency **≤.001%** in gnomAD subpopulation with the highest frequency
Evidence considered
  • ATM VCEP v1.6 CSPEC PM2 entry: Frequency ≤.001% in gnomAD subpopulation with the highest frequency; the VCEP specifies PM2 Supporting, not moderate.
  • gnomAD v2.1 all-comers result for ATM NM_000051.4:c.4424A>C: absent.
  • gnomAD v4.1 all-comers result for ATM NM_000051.4:c.4424A>C: absent; the available v2.1 non-cancer and v3.1 non-cancer results were also absent, but the VCEP does not require those subsets for PM2.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS3 SupportingVCEPMet at Supporting: direct prime-editing classified c.4424A>C as Functional with Medium-high confidence and DeepATM_predicted=No, satisfying the VCEP BS3 mapping. Details ▾Hide ▴
Reasoning

The exact Suppl_TableS1_PMID 40580951.xlsx row for c.4424A>C / Y1475S reports Classification=Functional, Confidence=Medium-high, and DeepATM_predicted=No. Under the VCEP's file-specific rule, this is a direct prime-editing measurement and Functional maps to BS3_Supporting. The governing ATM VCEP rule states: "Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity." The approved-assay calibration table was also searched under all three requested notations but has no variant-specific entry, so it cannot independently add strength or create a conflict.

VCEP rule
Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Evidence considered
  • Sun et al. 2025 Supplementary Table S1, matching row c.4424A>C / genomic position 108289789 A>C / Y1475S: Classification=Functional; Confidence=Medium-high; DeepATM_predicted=No.
  • The VCEP file-specific rule says DeepATM_predicted=No with Confidence High, Medium-high, or Medium is a direct prime-editing measurement; Functional maps to BS3_Supporting.
  • The ClinGen HBOP ATM approved functional-assay file was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no variant-specific entry was found.
Still missing
  • No entry for c.4424A>C, p.Tyr1475Ser, or p.Y1475S was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-calibration table, not a per-variant results table.
  • No variant-specific result from the three approved papers listed in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was available in the case literature extracts.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
BP4 SupportingVCEPMet at Supporting: SpliceAI max delta 0.005 is ≤0.1 for the VCEP's no-predicted-splice-impact BP4 path, despite REVEL 0.284. Details ▾Hide ▴
Reasoning

The ATM VCEP permits BP4 at Supporting strength through either the missense path, REVEL ≤.249, or the splicing path, no predicted splice impact by SpliceAI ≤0.1. This missense variant does not meet the protein path because REVEL is 0.284, but it meets the separately specified splicing path because the SpliceAI maximum delta score is 0.005, which is ≤0.1. The VCEP's rule does not require both paths to be satisfied, and the SpliceAI result is used once for BP4 only. The governing Supplementary Table S1 row for c.4424A>C (Y1475S) was found and reports Classification Functional, Confidence Medium-high, and DeepATM_predicted No; it does not pre-assign BP4 and is not needed to establish the BP4 threshold result.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • ATM VCEP v1.6 CSPEC BP4 Supporting rule: Missense REVEL ≤.249; splicing no predicted impact via SpliceAI ≤0.1.
  • Local REVEL lookup for ATM NM_000051.4:c.4424A>C / p.Tyr1475Ser: REVEL score 0.284, above the VCEP missense BP4 cutoff.
  • SpliceAI Lookup for NM_000051.4:c.4424A>C: DS_AG 0.002, DS_AL 0.000, DS_DG 0.002, DS_DL 0.005; maximum delta score 0.005, at or below the VCEP splicing BP4 cutoff.
  • Sun et al. 2025 Supplementary Table S1, row ATM c.4424A>C (Y1475S), genomic 108289789 A>C, exon_29, missense: Classification Functional; Confidence Medium-high; DeepATM_predicted No. The row was searched for a pre-assigned PP3/BP4 code and none was present.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Not met · 4 · evaluated, threshold not reached

PS3 VCEPNot met: direct prime-editing classified c.4424A>C as Functional with Medium-high confidence, opposite the VCEP PS3 requirement for failure to rescue an ATM-specific feature. Details ▾Hide ▴
Reasoning

The exact Suppl_TableS1_PMID 40580951.xlsx row for c.4424A>C / Y1475S reports Classification=Functional, Confidence=Medium-high, and DeepATM_predicted=No, which the VCEP file-specific rule defines as a direct prime-editing measurement supporting BS3_Supporting rather than PS3. The governing ATM VCEP rule states: "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". The separately governed ClinGen approved-assay methodology table contains no occurrence of c.4424A>C, p.Tyr1475Ser, or p.Y1475S and is not itself a variant-results table; therefore it provides no variant-specific damaging assay result for PS3.

VCEP rule
Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency
Evidence considered
  • Sun et al. 2025 Supplementary Table S1, matching row c.4424A>C / genomic position 108289789 A>C / Y1475S: Classification=Functional; Confidence=Medium-high; DeepATM_predicted=No.
  • The VCEP file-specific rule says DeepATM_predicted=No with Confidence High, Medium-high, or Medium is a direct prime-editing measurement; Functional maps to BS3_Supporting and Non-functional maps to PS3_Supporting.
  • The ClinGen HBOP ATM approved functional-assay file was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no variant-specific entry was found.
Still missing
  • No entry for c.4424A>C, p.Tyr1475Ser, or p.Y1475S was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-calibration table, not a per-variant results table.
  • No variant-specific result from the three approved papers listed in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was available in the case literature extracts.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗
PP3 VCEPNot met: REVEL 0.284 is below the >0.7333 PP3 threshold and SpliceAI max delta 0.005 is below the ≥0.2 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PP3 for this missense variant through either the missense path, REVEL >.7333, or the splicing path, SpliceAI ≥0.2 for missense/in-frame variants. REVEL is 0.284 and the SpliceAI maximum delta score is 0.005 (DS_AG 0.002, DS_AL 0.000, DS_DG 0.002, DS_DL 0.005), so neither VCEP threshold is met. The governing Supplementary Table S1 row for c.4424A>C (Y1475S) was found and reports Classification Functional, Confidence Medium-high, and DeepATM_predicted No; it does not pre-assign PP3 or BP4, and its functional classification is not substituted for a computational criterion.

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
  • ATM VCEP v1.6 CSPEC PP3 Supporting rule: Missense REVEL >.7333; splicing predicted impact via SpliceAI ≥0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
  • Local REVEL lookup for ATM NM_000051.4:c.4424A>C / p.Tyr1475Ser: REVEL score 0.284.
  • SpliceAI Lookup for NM_000051.4:c.4424A>C: DS_AG 0.002, DS_AL 0.000, DS_DG 0.002, DS_DL 0.005; maximum delta score 0.005.
  • Sun et al. 2025 Supplementary Table S1, row ATM c.4424A>C (Y1475S), genomic 108289789 A>C, exon_29, missense: Classification Functional; Confidence Medium-high; DeepATM_predicted No. This governing table row was searched for a pre-assigned PP3/BP4 code and none was present; the row was not used to replace the VCEP's PP3 thresholds.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BA1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP's >0.5% grpmax allele-frequency threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BA1 as a grpmax filtering allele frequency greater than 0.5% in gnomAD. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so the BA1 threshold is not reached. The VCEP does not require a non-cancer or exome-only subset for BA1; the default all-comers sources were therefore used.

VCEP rule
Grpmax Filtering AF **>.5%** in gnomAD
Evidence considered
  • ATM VCEP v1.6 CSPEC BA1 entry: Grpmax Filtering AF >.5% in gnomAD.
  • gnomAD v2.1 all-comers result for ATM NM_000051.4:c.4424A>C: absent.
  • gnomAD v4.1 all-comers result for ATM NM_000051.4:c.4424A>C: absent; the available v2.1 non-cancer and v3.1 non-cancer results were also absent, but the VCEP does not require those subsets for BA1.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 VCEPNot met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the VCEP's >0.05% grpmax allele-frequency threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BS1 as a grpmax filtering allele frequency greater than 0.05% in gnomAD. The variant is absent from gnomAD v2.1 and gnomAD v4.1, so the BS1 threshold is not reached. The VCEP does not require a non-cancer or exome-only subset for BS1; the default all-comers sources were therefore used.

VCEP rule
Grpmax Filtering AF **>.05%** in gnomAD
Evidence considered
  • ATM VCEP v1.6 CSPEC BS1 entry: Grpmax Filtering AF >.05% in gnomAD.
  • gnomAD v2.1 all-comers result for ATM NM_000051.4:c.4424A>C: absent.
  • gnomAD v4.1 all-comers result for ATM NM_000051.4:c.4424A>C: absent; the available v2.1 non-cancer and v3.1 non-cancer results were also absent, but the VCEP does not require those subsets for BS1.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 5 · no assessment recorded

PS1 VCEPNot assessed: no governing-table entry or established same-amino-acid pathogenic comparator was available for p.Tyr1475Ser, despite a maximum SpliceAI delta of 0.005. Details ▾Hide ▴
Reasoning

The variant is a missense change, and SpliceAI predicts a maximum delta score of 0.005, supporting no significant splice impact. The ATM PS1 guide requires the same amino-acid change as a previously established pathogenic variant and requires splice defects to be ruled out for both alterations. Searches of ATM_PS1_1.6.pdf.txt for c.4424A>C, p.Tyr1475Ser, and p.Y1475S found no entry for this variant, and the available case evidence contains no established pathogenic ATM variant with the same amino-acid change. 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 PS1 guide: the missense PS1 rule requires the same amino-acid change as a previously established pathogenic variant, with splice defect ruled out for both alterations.
  • ATM_PS1_1.6.pdf.txt was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no entry for this variant was found.
  • The case's SpliceAI result has DS_AG 0.002, DS_AL 0.000, DS_DG 0.002, DS_DL 0.005, with maximum delta 0.005.
Still missing
  • No entry for c.4424A>C, p.Tyr1475Ser, or p.Y1475S was found in ATM_PS1_1.6.pdf.txt; an established pathogenic ATM variant producing the same amino-acid change is still needed.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗spliceai ↗
PS4 VCEPNot assessed: no case-control paper or variant-specific affected-versus-control counts were available to calculate p-value, odds ratio, or 95% CI. Details ▾Hide ▴
Reasoning

The ATM VCEP requires a case-control study with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥2, or a lower 95% confidence interval ≥1.5. The available literature_pass.json contains zero PMIDs and no packet.ai_classified_papers; therefore, there is no variant-specific affected-versus-unaffected or population-control comparison from which to calculate an odds ratio or 95% confidence interval, and no p-value is available. PS4 cannot be evaluated from the available evidence.

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 CSPEC PS4 rule: Case-control studies; p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).
  • literature_pass.json reports total_pmids=0, with empty high_priority_papers, medium_priority_papers, criteria_index, and criterion_screened; no packet.ai_classified_papers or paper_extracts entries were available.
  • No case or control counts, p-value, odds ratio, hazard ratio, relative risk, or confidence interval for NM_000051.4:c.4424A>C were available.
Still missing
  • A variant-specific case-control study or affected-versus-matched-control counts with a p-value are required to evaluate PS4.
Sources
cspec ↗
PM3 VCEPNot assessed: no affected-proband, phenotype, second-variant, or phase evidence was available to assign the ATM VCEP's PM3 points. Details ▾Hide ▴
Reasoning

PM3 cannot be assessed because the case evidence contains no affected-proband observation, phenotype classification, second ATM variant, or phase information for NM_000051.4:c.4424A>C (p.Tyr1475Ser/p.Y1475S). The governing ATM_PM3_BP2_1.6.pdf was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no variant-specific entry or pre-assigned PM3 code was found. The case bundle likewise provides no allelic observation from which to assign PM3 points. Therefore, no PM3 strength is assigned.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, PM3 section and Ataxia Telangiectasia PM3/BP2 table: the governing table was searched under c.4424A>C, p.Tyr1475Ser, and p.Y1475S, with no matching variant row or pre-assigned PM3 code found.
  • criteria_evidence_bundle_allelic.txt: case materials identify NM_000051.4:c.4424A>C / p.Tyr1475Ser but contain no affected-proband, A-T phenotype, second ATM variant, or phase observation for this criterion.
  • ATM VCEP PM3 points table: without a documented proband observation and allelic configuration, no per-proband PM3 points can be assigned.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no variant-specific entry or pre-assigned PM3 code was found.
  • No affected-proband observation or confident/consistent Ataxia-Telangiectasia phenotype is documented in the case evidence.
  • No pathogenic/likely pathogenic ATM variant in trans, phase-unknown second variant, homozygous observation, or other allelic configuration is documented in the case evidence.
Sources
vcep_atm_pm3_bp2_1_6 ↗cspec ↗
PP1 VCEPNot assessed: no affected relatives or segregation data are available to evaluate the VCEP requirement that both variants be identified in the proband. Details ▾Hide ▴
Reasoning

PP1 has an applicable autosomal recessive path in the ATM VCEP, but the available case evidence contains no affected relatives, parental phase results, segregation observations, or meiosis count. The VCEP requires affected relatives to have both variants identified in the proband, so no PP1 strength can be assigned.

VCEP rule
AR Condition: Affected relatives must have both variants identified in proband.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PP1: the applicable AR path requires affected relatives to have both variants identified in the proband; the case materials report no family segregation data.
Still missing
  • Affected-relative identities and phenotypes
  • Variant testing in affected relatives
  • Parental testing and phase information
  • Number of informative meioses
Sources
cspec ↗
BP2 VCEPNot assessed: no unaffected-adult observation or cis/trans relationship with a pathogenic ATM variant was documented for BP2. Details ▾Hide ▴
Reasoning

BP2 cannot be assessed because the case evidence contains no unaffected adult observation, no evidence that NM_000051.4:c.4424A>C is in trans with a pathogenic or likely pathogenic ATM variant, and no evidence that it is in cis with a pathogenic variant. The governing ATM_PM3_BP2_1.6.pdf was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no variant-specific entry or pre-assigned BP2 code was found. Therefore, no BP2 points or strength are assigned.

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: the governing table was searched under c.4424A>C, p.Tyr1475Ser, and p.Y1475S, with no matching variant row or pre-assigned BP2 code found.
  • criteria_evidence_bundle_allelic.txt: case materials identify NM_000051.4:c.4424A>C / p.Tyr1475Ser but contain no unaffected-adult observation or cis/trans allelic relationship for this criterion.
  • ATM VCEP BP2 points table: no BP2 points can be assigned without the required unaffected-proband and allelic-configuration evidence.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no variant-specific entry or pre-assigned BP2 code was found.
  • No unaffected non-Ataxia-Telangiectasia adult observation meeting the VCEP's BP2 context is documented.
  • No cis or trans relationship between this variant and a pathogenic/likely pathogenic ATM variant is documented.
Sources
vcep_atm_pm3_bp2_1_6 ↗cspec ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.4424A>C is a missense variant, whereas the ATM PVS1 rule applies to specified null-variant classes. Details ▾Hide ▴
Reasoning

NM_000051.4:c.4424A>C produces the missense substitution NP_000042.3:p.(Tyr1475Ser) in exon 29, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. The ATM VCEP PVS1 guide defines PVS1 for null variant classes and therefore does not apply PVS1 to this missense change. The required variant searches found no c.4424A>C, p.Tyr1475Ser, or p.Y1475S entry in ATM_PVS1_1.6.pdf.txt; this is a search result, not evidence that loss of function is absent.

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease
Evidence considered
  • Case normalization: NM_000051.4:c.4424A>C gives NP_000042.3:p.(Tyr1475Ser) / p.(Y1475S), and the consequence assessment identifies exon 29 and missense consequence.
  • ATM_PVS1_1.6.pdf.txt, opening PVS1 definition: the rule is for a null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function is a known mechanism of disease.
  • ATM_PVS1_1.6.pdf.txt was searched for c.4424A>C, p.Tyr1475Ser, and p.Y1475S; no matching variant-specific row was found.
Still missing
  • No c.4424A>C, p.Tyr1475Ser, or p.Y1475S entry was found in ATM_PVS1_1.6.pdf.txt; the general VCEP rule was available and sufficient to determine non-applicability.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗
PS2 VCEPNot applicable: the ATM VCEP prohibits PS2 for both dominant and recessive disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

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

VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PS2: applicability is Not applicable; instruction states not to use PS2 for AD or AR disease because informative de novo occurrences have not yet been observed.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP marks PM1 Not Applicable, and its authoritative domain_tables entry is empty for this gene. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC marks PM1 as Not Applicable. The authoritative vcep_materials.json domain_tables key is present but empty, so no VCEP-approved critical functional domain list supplies a PM1 route for residue 1475.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC criterion entry for PM1: applicability is Not Applicable.
  • vcep_materials.json domain_tables: {}.
Sources
cspec ↗
PM4 N/ANot applicable: p.Tyr1475Ser is a missense substitution, not the stop-loss variant type specified by the ATM VCEP PM4 rule. Details ▾Hide ▴
Reasoning

The ATM VCEP PM4 rule is limited to stop-loss variants. NM_000051.4:c.4424A>C is a missense substitution yielding p.(Tyr1475Ser), with no protein-length extension or stop-loss consequence, so PM4 is not applicable.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • Case normalization identifies NM_000051.4:c.4424A>C as p.(Tyr1475Ser), a missense substitution with no protein-length change.
  • ATM VCEP CSPEC PM4 entry specifies: Use 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 variant is missense p.Tyr1475Ser. Details ▾Hide ▴
Reasoning

The ATM VCEP PM5 rule is limited to NMD-prone truncating DNA variants receiving PVS1 Very Strong, or observed NMD-prone truncating splice variants receiving PVS1(RNA) Very Strong with high-quality RNA data, with premature termination codons upstream of p.Leu3048. This variant is missense p.Tyr1475Ser, so it is outside the rule's applicability.

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 PM5 Supporting rule: DNA variants must be NMD-prone truncating variants with PVS1 Very Strong and premature termination codons upstream of p.Leu3048; the separate splice route requires observed RNA evidence and PVS1(RNA) Very Strong.
  • Case normalization identifies NM_000051.4:c.4424A>C as missense p.Tyr1475Ser in exon 29.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP prohibits PM6 for both dominant and recessive disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PM6 not applicable and explicitly prohibits its use for both autosomal dominant and autosomal recessive disease because informative de novo occurrences have not been observed and de novo recessive conditions are unlikely to be informed by phase.

VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for PM6: applicability is Not applicable; instruction states not to use PM6 for AD or AR disease because informative de novo occurrences have not yet been observed.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP explicitly designates PP2 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC explicitly marks PP2 as Not Applicable; no PP2 assessment is permitted under the governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC criterion entry for PP2: applicability is Not Applicable.
Sources
cspec ↗
PP4 VCEPNot applicable: the ATM VCEP v1.6 criterion entry explicitly marks PP4 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC criterion entry explicitly marks PP4 as Not Applicable; no PP4 phenotype-specificity assessment is permitted under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criterion entry for PP4: Applicability = Not Applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP v1.6 criterion entry explicitly marks PP5 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC criterion entry explicitly marks PP5 as Not Applicable; no PP5 assertion based on another source's pathogenic classification is permitted under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criterion entry for PP5: Applicability = Not Applicable.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP prohibits BS2 because ATM has incomplete penetrance. Details ▾Hide ▴
Reasoning

BS2 is not applicable under the ATM VCEP because the VCEP explicitly instructs: Do not use: ATM has incomplete penetrance. Therefore, available homozygote or healthy-adult observations cannot activate BS2 for this interpretation.

VCEP rule
Do not use: ATM has incomplete penetrance.
Evidence considered
  • ATM VCEP v1.6 CSPEC BS2 entry: Do not use: ATM has incomplete penetrance.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP excludes BS4 because informative lack-of-co-segregation instances in ataxia-telangiectasia families are too rare for weight. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS4 not applicable. Its specifications state that informative lack-of-co-segregation instances in ataxia-telangiectasia families are too rare to receive weight at this time.

VCEP rule
AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC entry for BS4: applicability is Not applicable; AR guidance states that informative lack-of-co-segregation instances in A-T families are too rare to be considered for weight.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP explicitly designates BP1 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC explicitly marks BP1 as Not Applicable; no BP1 assessment is permitted under the governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC criterion entry for BP1: applicability is Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP explicitly marks BP3 as not applicable, and this variant is missense rather than an in-frame repeat-region indel. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC entry marks BP3 as Not Applicable. In addition, this variant is a missense substitution rather than an in-frame deletion or insertion in a repetitive region, so BP3 cannot be applied under this VCEP framework.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC BP3 entry explicitly lists applicability as Not Applicable.
  • Case normalization identifies NM_000051.4:c.4424A>C as the missense substitution p.(Tyr1475Ser), not an in-frame deletion or insertion.
  • No BP3-specific VCEP variant table was declared for this case.
Sources
cspec ↗
BP5 VCEPNot applicable: the ATM VCEP v1.6 criterion entry explicitly marks BP5 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC criterion entry explicitly marks BP5 as Not Applicable; no BP5 evidence assessment is permitted under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criterion entry for BP5: Applicability = Not Applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP v1.6 criterion entry explicitly marks BP6 as Not Applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 CSPEC criterion entry explicitly marks BP6 as Not Applicable; no BP6 assertion based on another source's benign classification is permitted under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criterion entry for BP6: Applicability = Not Applicable.
Sources
cspec ↗
BP7 N/ANot applicable: c.4424A>C is an exonic missense variant, while the VCEP limits BP7 to synonymous and deep intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the ATM VCEP to synonymous and deep intronic variants, including deep intronic variants beyond but not including +7 at donor sites and -21 at acceptor sites. NM_000051.4:c.4424A>C is an exonic missense variant producing p.Tyr1475Ser, so BP7 is outside its governing scope regardless of the available SpliceAI result.

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
  • ATM VCEP v1.6 CSPEC BP7 Supporting rule: use BP7 for synonymous and deep intronic variants further than but not including +7 donor and -21 acceptor positions.
  • Variant normalization: NM_000051.4:c.4424A>C is an exon 29 missense substitution, NP_000042.3:p.(Tyr1475Ser).
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.4424A>C
Protein (HGVS p.)
NP_000042.3:p.(Tyr1475Ser)
GRCh38
chr11:108289789 A>C
GRCh37
chr11:108160516 A>C
Location and type
Exon 29 · missense

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 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +255 bp
0.000
SpliceAI acceptor gainat -187 bp
0.002
SpliceAI donor lossat -157 bp
0.005
SpliceAI donor gainat +12 bp
0.002
Pangolin splice lossmagnitude shown
-0.003
Pangolin splice gain
0.012

Other predictors

REVEL
0.284
BayesDel
-0.203

How the predictions were used

BP4 SupportingVCEPMet at Supporting: SpliceAI max delta 0.005 is ≤0.1 for the VCEP's no-predicted-splice-impact BP4 path, despite REVEL 0.284. Details ▾Hide ▴
Reasoning

The ATM VCEP permits BP4 at Supporting strength through either the missense path, REVEL ≤.249, or the splicing path, no predicted splice impact by SpliceAI ≤0.1. This missense variant does not meet the protein path because REVEL is 0.284, but it meets the separately specified splicing path because the SpliceAI maximum delta score is 0.005, which is ≤0.1. The VCEP's rule does not require both paths to be satisfied, and the SpliceAI result is used once for BP4 only. The governing Supplementary Table S1 row for c.4424A>C (Y1475S) was found and reports Classification Functional, Confidence Medium-high, and DeepATM_predicted No; it does not pre-assign BP4 and is not needed to establish the BP4 threshold result.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • ATM VCEP v1.6 CSPEC BP4 Supporting rule: Missense REVEL ≤.249; splicing no predicted impact via SpliceAI ≤0.1.
  • Local REVEL lookup for ATM NM_000051.4:c.4424A>C / p.Tyr1475Ser: REVEL score 0.284, above the VCEP missense BP4 cutoff.
  • SpliceAI Lookup for NM_000051.4:c.4424A>C: DS_AG 0.002, DS_AL 0.000, DS_DG 0.002, DS_DL 0.005; maximum delta score 0.005, at or below the VCEP splicing BP4 cutoff.
  • Sun et al. 2025 Supplementary Table S1, row ATM c.4424A>C (Y1475S), genomic 108289789 A>C, exon_29, missense: Classification Functional; Confidence Medium-high; DeepATM_predicted No. The row was searched for a pre-assigned PP3/BP4 code and none was present.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP3 VCEPNot met: REVEL 0.284 is below the >0.7333 PP3 threshold and SpliceAI max delta 0.005 is below the ≥0.2 threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PP3 for this missense variant through either the missense path, REVEL >.7333, or the splicing path, SpliceAI ≥0.2 for missense/in-frame variants. REVEL is 0.284 and the SpliceAI maximum delta score is 0.005 (DS_AG 0.002, DS_AL 0.000, DS_DG 0.002, DS_DL 0.005), so neither VCEP threshold is met. The governing Supplementary Table S1 row for c.4424A>C (Y1475S) was found and reports Classification Functional, Confidence Medium-high, and DeepATM_predicted No; it does not pre-assign PP3 or BP4, and its functional classification is not substituted for a computational criterion.

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
  • ATM VCEP v1.6 CSPEC PP3 Supporting rule: Missense REVEL >.7333; splicing predicted impact via SpliceAI ≥0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.
  • Local REVEL lookup for ATM NM_000051.4:c.4424A>C / p.Tyr1475Ser: REVEL score 0.284.
  • SpliceAI Lookup for NM_000051.4:c.4424A>C: DS_AG 0.002, DS_AL 0.000, DS_DG 0.002, DS_DL 0.005; maximum delta score 0.005.
  • Sun et al. 2025 Supplementary Table S1, row ATM c.4424A>C (Y1475S), genomic 108289789 A>C, exon_29, missense: Classification Functional; Confidence Medium-high; DeepATM_predicted No. This governing table row was searched for a pre-assigned PP3/BP4 code and none was present; the row was not used to replace the VCEP's PP3 thresholds.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 N/ANot applicable: c.4424A>C is an exonic missense variant, while the VCEP limits BP7 to synonymous and deep intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the ATM VCEP to synonymous and deep intronic variants, including deep intronic variants beyond but not including +7 at donor sites and -21 at acceptor sites. NM_000051.4:c.4424A>C is an exonic missense variant producing p.Tyr1475Ser, so BP7 is outside its governing scope regardless of the available SpliceAI result.

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
  • ATM VCEP v1.6 CSPEC BP7 Supporting rule: use BP7 for synonymous and deep intronic variants further than but not including +7 donor and -21 acceptor positions.
  • Variant normalization: NM_000051.4:c.4424A>C is an exon 29 missense substitution, NP_000042.3:p.(Tyr1475Ser).
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.284. BayesDel score = -0.202632.

0 paper records listed. 1 cited in the classification.

Cited in the classification

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.005 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.284. BayesDel score = -0.202632.

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.