0%
ATMc.5937A>GLikely benign
Print report
Variant interpretation report

ATM c.5937A>G, p.(Glu1979=)

NM_000051.4:c.5937A>G NP_000042.3:p.(Glu1979=) Synonymous · exon 40 View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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: 2 Benign evidence criteria: 2
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

Met at Supporting: variant absent from gnomAD v2.1/v4.1 and non-cancer subsets, satisfying ATM VCEP's ≤0.001% highest-subpopulation frequency rule.

PP3Supporting
PP3 · supporting

Met at supporting: SpliceAI maximum delta 0.247 meets the ATM VCEP PP3 threshold of >=0.2 for predicted splice impact.

Benign criteria applied · 2
BS3Supporting
BS3 · supporting

Met, Supporting: direct prime-editing data classify c.5937A>G as Functional with high confidence, but VCEP acceptance of this non-approved assay requires human review.

BP7Supporting
BP7 · supporting

Met at supporting: ATM VCEP v1.6 assigns BP7 supporting to synonymous variants, and this variant is c.5937A>G (p.Glu1979=).

Recorded classification: Likely benign

Likely Benign: BS3 (supporting) and BP7 (supporting) satisfy ATM VCEP Version 1.6 Rule19; PM2 and PP3 are additionally applied at supporting strength.

02The sources

Evidence at a glance

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

SpliceAI score
0.247 maximum delta

Recorded SpliceAI maximum delta score: 0.247. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3, BP7 → SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

2 Likely benign · 1 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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: 4 met · 4 not met · 5 not assessed · 15 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 NM_000051.4:c.5937A>G is synonymous and lacks observed RNA evidence for the ATM PVS1(RNA) pathway.

PM4 is not applicable because the ATM VCEP limits it to stop-loss variants, and BP3 is explicitly marked Not Applicable by the ATM VCEP.

For the requested codon/residue/domain criteria, only PS1 has a potentially relevant splice-path question; it remains not assessed because the required matching pathogenic reference splice event is unavailable.

PM1, PM5, PP2, and BP1 are not applicable under the governing ATM VCEP framework and the synonymous consequence.

The applicable ATM HBOP VCEP v1.6 framework governs this variant and explicitly designates PP4, PP5, BP5, and BP6 as Not Applicable.

PS4 is applicable in the framework, but cannot be assessed because no variant-specific case-control statistics were found.

The ClinVar record is an exact variant match but contains zero expert-panel submissions, so its ordinary laboratory assertions do not activate PP5 or BP6.

The variant is synonymous, so PP3 and BP4 were evaluated only through SpliceAI and BP7 was evaluated under the ATM VCEP synonymous-variant rule.

SpliceAI maximum delta 0.247 meets PP3 supporting (>=0.2) but exceeds the BP4 no-impact threshold (<=0.1) and is inconsistent with standard BP7.

The exact variant was searched in the governing ATM VCEP full-text files. Suppl_TableS1_PMID 40580951.xlsx contains c.5937A>G as a synonymous exon 40 row with Classification Functional, Confidence High, and DeepATM_predicted No, but it does not provide a pre-assigned PP3, BP4, or BP7 code and was not used as functional evidence for these criteria.

Met · 4

PM2 SupportingMet at Supporting: variant absent from gnomAD v2.1/v4.1 and non-cancer subsets, satisfying ATM VCEP's ≤0.001% highest-subpopulation frequency rule. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 applies PM2 only at Supporting strength and requires frequency no greater than 0.001% in the gnomAD subpopulation with the highest frequency, with a single-observation exception. 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 gnomAD v3.1 non-cancer datasets. Therefore, its observed frequency is 0 in the available population datasets and satisfies the VCEP PM2 Supporting threshold.

Rule
ATM VCEP v1.6: PM2 Supporting requires frequency ≤0.001% in the highest-frequency gnomAD subpopulation; absence qualifies.
Evidence considered
  • ATM VCEP version 1.6 defines PM2 Supporting as frequency ≤0.001% in the gnomAD subpopulation with the highest frequency; it also permits the criterion when a variant is absent.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1, and absent from the available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer datasets.
  • The available population observations therefore support an allele frequency of 0 in these datasets, below the VCEP threshold.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
PP3 SupportingMet at supporting: SpliceAI maximum delta 0.247 meets the ATM VCEP PP3 threshold of >=0.2 for predicted splice impact. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_000051.4:c.5937A>G; NP_000042.3:p.(Glu1979=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI reports a maximum delta score of 0.247 (DS_AL 0.247), which meets the ATM VCEP v1.6 PP3 supporting threshold of >=0.2 for predicted splice impact in silent variants. The ATM VCEP PP3 rule is applied directly; the governing VCEP materials contain no per-variant pre-assigned PP3 code for c.5937A>G.

Rule
ATM VCEP v1.6 PP3 Supporting: Splicing—predicted impact via SpliceAI >=0.2 for silent variants.
Evidence considered
  • ATM VCEP version 1.6 specifies PP3 supporting for silent variants with predicted splice impact by SpliceAI >=0.2.
  • SpliceAI for NM_000051.4:c.5937A>G reports DS_AG 0.002, DS_AL 0.247, DS_DG 0.000, and DS_DL 0.157; the maximum delta is 0.247.
  • The searched ATM VCEP file Suppl_TableS1_PMID 40580951.xlsx contains the exact c.5937A>G row but does not pre-assign PP3 or BP4 and has NA predictor fields for this synonymous row.
Sources
cspec ↗spliceai ↗
BS3 SupportingMet, Supporting: direct prime-editing data classify c.5937A>G as Functional with high confidence, but VCEP acceptance of this non-approved assay requires human review. Details ▾Hide ▴
Reasoning

The ATM VCEP specifies BS3_Supporting when a variant rescues either an ATM-specific feature or radiosensitivity, and BS3_Moderate when it rescues both. The governing approved-assay methodology file contains no entry for c.5937A>G, p.Glu1979=, or p.E1979=, so no approved VCEP assay result can be assigned directly. Sun et al. Table S1 directly measures this variant through the prime-editing screen (DeepATM_predicted=No) and reports Classification=Functional with Confidence=High and Combined_score=0.119400150926129, supporting retained normal ATM function and therefore a tentative BS3_Supporting assignment. Because this post-VCEP assay is not one of the VCEP-approved assays, human review is required before treating BS3_Supporting as specification-compliant.

Rule
ATM VCEP BS3: Moderate requires rescue of both an ATM-specific feature and radiosensitivity; Supporting requires rescue of either an ATM-specific feature or radiosensitivity.
Evidence considered
  • ATM VCEP BS3: use Moderate when a variant rescues both an ATM-specific feature and radiosensitivity, and Supporting when it rescues either an ATM-specific feature or radiosensitivity.
  • Table S1 row 18967 for c.5937A>G / E1979E reports Variant_consequence=Synonymous, Combined_score=0.119400150926129, Classification=Functional, Confidence=High, and DeepATM_predicted=No.
  • DeepATM_predicted=No indicates that the Table S1 classification is based on the underlying prime-editing saturation genome-editing measurement rather than a computational extrapolation.
  • The result is assigned tentatively at BS3_Supporting because it supports retained function, while the VCEP-approved-assay limitation triggers human review.
Still missing
  • The approved-assay methodology file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.5937A>G, p.Glu1979=, and p.E1979=; no variant-specific entry was found.
  • No variant-specific kinase-activity or radiosensitivity result from the ATM VCEP-approved papers PMID:18634022, PMID:19431188, or PMID:11805335 was supplied for this variant.
  • Human review is required to confirm that the Sun et al. 2025 prime-editing functional screen is acceptable evidence for ATM BS3 under the current VCEP specification.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP7 SupportingMet at supporting: ATM VCEP v1.6 assigns BP7 supporting to synonymous variants, and this variant is c.5937A>G (p.Glu1979=). Details ▾Hide ▴
Reasoning

BP7 is in scope because the variant is synonymous. The ATM VCEP v1.6 directly specifies BP7 supporting for synonymous variants; its instructions also state that BP7 is not considered conflicting evidence against a body of evidence supporting a pathogenic splice defect. Therefore BP7 supporting applies from the synonymous consequence, independently of the SpliceAI PP3 result. No stronger BP7(RNA) level was assigned because no variant-specific RNA study demonstrating lack of an aberrant splice defect was identified.

Rule
ATM VCEP v1.6 BP7 Supporting: synonymous and deep intronic variants; BP7(RNA) separately requires observed lack of an aberrant RNA defect.
Evidence considered
  • ATM VCEP version 1.6 specifies BP7 supporting for synonymous variants and states that BP7 is not considered conflicting evidence against a body of evidence supporting a pathogenic splice defect.
  • NM_000051.4:c.5937A>G is annotated as synonymous, producing NP_000042.3:p.(Glu1979=).
  • No variant-specific RNA evidence demonstrating lack of an aberrant splice defect was present, so BP7(RNA) was not assigned at a stronger variable strength.
Sources
cspec ↗spliceai ↗

Not met · 4 · evaluated, threshold not reached

PS3 Not met: Table S1 classifies c.5937A>G as Functional with high confidence, not as a loss-of-function result qualifying for ATM PS3. Details ▾Hide ▴
Reasoning

The ATM VCEP specifies PS3 for a variant that fails to rescue an ATM-specific feature, with PS3_Supporting for failure of kinase activity alone and PS3_Moderate only when both an ATM-specific feature and radiosensitivity are abnormal; radiosensitivity alone has no weight. The governing approved-assay methodology file contains no entry for c.5937A>G, p.Glu1979=, or p.E1979=, and the three named approved papers (PMID:18634022, PMID:19431188, and PMID:11805335) therefore do not provide confirmed tested-variant evidence for this case. Sun et al. Table S1 does contain c.5937A>G and reports Classification=Functional, Confidence=High, and DeepATM_predicted=No, which is direct prime-editing functional evidence consistent with retained rather than lost function; however, this assay is not one of the ATM VCEP-approved assays and cannot establish PS3 under the current specification. PS3 is therefore not met.

Rule
ATM VCEP PS3: Strong is not used; Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity; Supporting requires failure to rescue an ATM-specific feature alone; radiosensitivity-only evidence receives no weight.
Evidence considered
  • ATM VCEP PS3: use Moderate when a variant fails to rescue both an ATM-specific feature and radiosensitivity; use Supporting when it fails to rescue an ATM-specific feature only, and do not use radiosensitivity alone.
  • The approved ATM functional-assay table names kinase-activity assays in PMID:18634022, PMID:19431188, and PMID:11805335, but is a calibration table rather than a per-variant results table.
  • Table S1 row 18967 for c.5937A>G / E1979E reports Variant_consequence=Synonymous, Combined_score=0.119400150926129, Classification=Functional, Confidence=High, and DeepATM_predicted=No.
  • Because the Sun et al. assay is not among the VCEP-approved assays, its direct functional result is recorded as human-review material rather than silently converted into an ATM PS3 strength.
Still missing
  • The approved-assay methodology file clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx was searched for c.5937A>G, p.Glu1979=, and p.E1979=; no variant-specific entry was found.
  • The approved ATM assay papers PMID:18634022, PMID:19431188, and PMID:11805335 were not identified as variant-specific evidence for this synonymous variant in the supplied case evidence.
  • Human review is required to determine whether the Sun et al. 2025 prime-editing assay can be accepted under the current ATM VCEP specification; it is not an approved assay listed by the VCEP.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BA1 Not met: gnomAD v2.1 and v4.1 report the variant as absent, not a group maximum filtering allele frequency above 0.5%. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 specifies BA1 when the gnomAD group maximum filtering allele frequency is greater than 0.5%. The variant is absent from gnomAD v2.1 and gnomAD v4.1, with no population allele frequency or group maximum above that threshold. The gnomAD v2.1 non-cancer subset is also absent, so there is no basis for BA1.

Rule
ATM VCEP v1.6: BA1 requires gnomAD group maximum filtering AF >0.5%.
Evidence considered
  • ATM VCEP version 1.6 defines BA1 as group maximum filtering allele frequency greater than 0.5% in gnomAD.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; the available gnomAD v2.1 non-cancer subset is also absent.
  • Because the variant is absent rather than observed above the VCEP threshold, BA1 is not met.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BS1 Not met: gnomAD v2.1 and v4.1 report the variant as absent, not a group maximum filtering allele frequency above 0.05%. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.6 specifies BS1 when the gnomAD group maximum filtering allele frequency is greater than 0.05%. The variant is absent from gnomAD v2.1 and gnomAD v4.1, with no population allele frequency or group maximum above that threshold. The gnomAD v2.1 non-cancer subset is also absent, so BS1 is not met.

Rule
ATM VCEP v1.6: BS1 requires gnomAD group maximum filtering AF >0.05%.
Evidence considered
  • ATM VCEP version 1.6 defines BS1 as group maximum filtering allele frequency greater than 0.05% in gnomAD.
  • The variant is reported absent from gnomAD v2.1 and gnomAD v4.1; the available gnomAD v2.1 non-cancer subset is also absent.
  • Because the variant is absent rather than observed above the VCEP threshold, BS1 is not met.
Sources
cspec ↗gnomad_v2 ↗gnomad_v4 ↗
BP4 Not met: SpliceAI maximum delta 0.247 exceeds the ATM VCEP BP4 no-impact threshold of <=0.1. Details ▾Hide ▴
Reasoning

The variant is synonymous, so BP4 must use the SpliceAI path and cannot use REVEL. The ATM VCEP v1.6 BP4 supporting threshold for no predicted splice impact is SpliceAI <=0.1, but the observed maximum delta is 0.247. Therefore BP4 is not met; the applicable splice prediction instead reaches the PP3 threshold.

Rule
ATM VCEP v1.6 BP4 Supporting: Splicing—no predicted impact via SpliceAI <=0.1.
Evidence considered
  • ATM VCEP version 1.6 specifies BP4 supporting for silent/splicing variants with no predicted splice impact by SpliceAI <=0.1.
  • SpliceAI for NM_000051.4:c.5937A>G reports a maximum delta score of 0.247, above the BP4 cutoff.
  • REVEL was not evaluated because this is a synonymous variant and the governing one-path rule assigns synonymous variants to SpliceAI.
Sources
cspec ↗spliceai ↗

Not assessed · 5 · no assessment recorded

PS1 Not assessed: SpliceAI max delta 0.247 exceeds the 0.2 splice-impact threshold, but no matching pathogenic reference event was found for the VCEP PS1 comparison. Details ▾Hide ▴
Reasoning

The ATM VCEP PS1 specification permits standard PS1 for the same amino-acid change in missense variants only when splicing is ruled out, or a splice-path PS1 code when the variant under assessment and a known pathogenic/likely pathogenic reference variant have precisely matching predicted splice events and adequate comparative prediction strength. NM_000051.4:c.5937A>G is synonymous, and SpliceAI reports a maximum delta of 0.247, meeting the generic supporting PP3 splice-impact threshold of 0.2 but not establishing a specific splice event. Direct searches of ATM_PS1_1.5.pdf.txt for c.5937A>G, p.Glu1979=, and p.E1979= found no reference entry for this variant; therefore the required VCEP comparator and matching-event evidence are unavailable, so PS1 cannot be assigned.

Rule
ATM VCEP PS1: standard missense PS1 requires the same amino-acid change with splicing ruled out; splice PS1 requires a precisely matching predicted event and comparable or stronger prediction strength.
Evidence considered
  • ATM VCEP PS1 requires the same amino-acid change for the missense path, with splicing ruled out, or a precisely matching predicted splice event and adequate prediction strength for the splice path.
  • The case normalization identifies NM_000051.4:c.5937A>G as synonymous, encoding p.Glu1979= / p.E1979=.
  • SpliceAI maximum delta is 0.247; this exceeds the supplied generic splice-impact threshold of 0.2, but no exact predicted splice event is reported.
  • Searches of ATM_PS1_1.5.pdf.txt for c.5937A>G, p.Glu1979=, and p.E1979= found no entry for this variant.
Still missing
  • ATM_PS1_1.5.pdf.txt contains no entry for c.5937A>G, p.Glu1979=, or p.E1979=; no VCEP-established pathogenic/likely pathogenic reference variant with the same predicted splice event was identified.
  • The specific splice event predicted for this synonymous variant is not provided, preventing the required precise event comparison.
Sources
cspec ↗spliceai ↗vcep_atm_ps1_1_5
PS4 Not assessed: no variant-specific case-control study, p-value, odds ratio, relative risk, hazard ratio, or confidence interval is available. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.6 specifies PS4 at Strong when a case-control study has p-value <=.05 and either an odds ratio, hazard ratio, or relative risk >=2 or a lower 95% confidence interval >=1.5. The case materials contain no variant-specific case-control cohort, p-value, effect estimate, or confidence interval for NM_000051.4:c.5937A>G, and the reviewed literature does not report this exact variant. Therefore PS4 cannot be assessed; no numeric comparison is available.

Rule
Case-control studies; p-value <=.05 and (Odds ratio, hazard ratio, or relative risk >=2 or lower 95% CI >=1.5).
Evidence considered
  • ATM HBOP VCEP v1.6 PS4 rule: case-control studies require p-value <=.05 and (odds ratio, hazard ratio, or relative risk >=2 or lower 95% confidence interval >=1.5).
  • No exact-variant case-control statistics were present for NM_000051.4:c.5937A>G; the reviewed candidate papers were unrelated guidelines or did not mention the variant.
Still missing
  • A variant-specific case-control study with p-value and odds ratio, hazard ratio, relative risk, or lower 95% confidence interval is unavailable.
Sources
cspec ↗PMID:24366402 ↗PMID:24418350 ↗PMID:31429903 ↗PMID:34012068 ↗
PM3 Not assessed: no affected-proband, homozygous, second-allele, or phase observation was available to assign the VCEP's PM3 points. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM PM3/BP2 specification requires scored observations of this variant in unrelated affected Ataxia-Telangiectasia probands, with weight determined by phenotype confidence and phase: 4.0 points for a confident phenotype confirmed in trans, 2.0 points with phase unknown, 1.0 point when the second variant is unidentified or a VUS, or 2.0 points for a homozygous affected individual, with consistent-phenotype values at half strength. The complete case evidence contains no affected-proband observation, homozygous observation, second ATM allele, pathogenic/likely pathogenic allele, phase information, or segregation data for NM_000051.4:c.5937A>G (p.Glu1979= / p.E1979=), so no PM3 points or strength can be assigned. The exact variant was not found in the governing file ATM_PM3_BP2_1.5.pdf.

Rule
PM3_VeryStrong >= 8 points; PM3_Strong = 4 points; PM3 = 2 points; PM3_Supporting = 1 point, using the ATM PM3/BP2 points table.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 assigns PM3 points for unrelated A-T probands according to phenotype confidence and phase: confident phenotype 4.0 points confirmed in trans, 2.0 phase unknown, 1.0 with a second variant unidentified or VUS, and 2.0 for a homozygous affected individual; consistent phenotype receives half these values.
  • The case evidence reviewed for NM_000051.4:c.5937A>G (p.Glu1979= / p.E1979=) contains no qualifying affected-proband, homozygous, second-allele, phase, or segregation observation.
  • A direct search of ATM_PM3_BP2_1.5.pdf for c.5937A>G, p.Glu1979=, and p.E1979= found no variant-specific entry.
Still missing
  • No affected Ataxia-Telangiectasia proband observation with phenotype classification was identified.
  • No pathogenic or likely pathogenic ATM allele and no phase or segregation information were identified.
  • No entry for c.5937A>G, p.Glu1979=, or p.E1979= was found in ATM_PM3_BP2_1.5.pdf.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 Not assessed: no affected-relative segregation, parental testing, or meiosis count is documented for applying the ATM VCEP PP1 thresholds. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PP1 for autosomal recessive disease according to affected-relative segregation, assigning supporting strength for one affected relative, moderate for two, and strong for at least three. The available case evidence contains no documented affected relatives, parental testing, segregation observations, or meioses for this variant, so PP1 cannot be assigned.

Rule
AR condition: segregation in 1 affected relative = supporting; 2 affected relatives = moderate; at least 3 affected relatives = strong.
Evidence considered
  • ClinGen HBOP ATM VCEP version 1.6 specifies PP1 supporting for segregation in one affected relative, moderate for two, and strong for at least three affected relatives in an autosomal recessive condition.
  • No documented affected-relative segregation, parental testing, or informative meioses for NM_000051.4:c.5937A>G were found in the available case evidence.
Still missing
  • Documented segregation results for affected relatives, including the number of informative meioses and parental genotypes, are unavailable.
Sources
cspec ↗
BP2 Not assessed: no unaffected adult co-occurrence with a pathogenic ATM allele or phase evidence was available to assign the VCEP's BP2 points. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM PM3/BP2 specification requires scored observations of this variant in unaffected non-A-T adults carrying a pathogenic or likely pathogenic ATM variant in trans: -4.0 points when trans is confirmed, -2.0 points when phase is unknown, or -2.0 points in a laboratory-setting homozygous observation and -1.0 point in a database-setting homozygous observation, with a maximum of -2.0 homozygous points. The complete case evidence contains no unaffected adult co-occurrence, pathogenic/likely pathogenic ATM allele, homozygous observation, phase information, or cis/trans evidence for NM_000051.4:c.5937A>G (p.Glu1979= / p.E1979=), so no BP2 points or strength can be assigned. The exact variant was not found in the governing file ATM_PM3_BP2_1.5.pdf.

Rule
BP2_Strong <= -4 points; BP2_Moderate = -2 points; BP2_Supporting = -1 point, using the ATM PM3/BP2 points table.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 assigns BP2 points for unaffected non-A-T adults carrying the variant with a pathogenic or likely pathogenic ATM variant in trans: -4.0 points confirmed in trans, -2.0 points phase unknown, and homozygous observations of -2.0 points in a laboratory setting or -1.0 point in a database setting.
  • The case evidence reviewed for NM_000051.4:c.5937A>G (p.Glu1979= / p.E1979=) contains no qualifying unaffected-adult co-occurrence, pathogenic/likely pathogenic ATM allele, homozygous, phase, or cis/trans observation.
  • A direct search of ATM_PM3_BP2_1.5.pdf for c.5937A>G, p.Glu1979=, and p.E1979= found no variant-specific entry.
Still missing
  • No unaffected non-A-T adult carrying this variant with a pathogenic or likely pathogenic ATM variant was identified.
  • No cis/trans phase information or qualifying homozygous observation was identified.
  • No entry for c.5937A>G, p.Glu1979=, or p.E1979= was found in ATM_PM3_BP2_1.5.pdf.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.5937A>G is synonymous (p.Glu1979=), while the ATM PVS1 guide covers null variants and no observed RNA defect is available. Details ▾Hide ▴
Reasoning

NM_000051.4:c.5937A>G is a synonymous variant, NP_000042.3:p.(Glu1979=) / p.(E1979=), rather than a nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, or exon-deletion null variant. The governing ClinGen HBOP ATM PVS1 guide (v1.5) limits its baseline PVS1 scope to those null consequences and notes that observed splice defects use PVS1(RNA); this case provides no observed RNA defect. SpliceAI predicts a max delta of 0.247, but that computational prediction alone does not convert a synonymous substitution into a PVS1-eligible null variant. Therefore PVS1 is not applicable.

Rule
ClinGen HBOP ATM PVS1 v1.5 null-variant scope; synonymous variants require observed splice evidence for the PVS1(RNA) pathway.
Evidence considered
  • The normalized annotation is NM_000051.4:c.5937A>G, NP_000042.3:p.(Glu1979=) / p.(E1979=), with synonymous consequence.
  • ATM_PVS1_1.5.pdf states that PVS1 is for nonsense, frameshift, canonical +/-1,2 splice-site, initiation-codon, and single- or multi-exon deletion variants.
  • ATM_PVS1_1.5.pdf states that PVS1(RNA) is used for observed splice defects; the case has no observed RNA result.
  • SpliceAI max delta is 0.247, which is computational splice prediction only and is insufficient by itself to establish PVS1(RNA).
Still missing
  • No exact c.5937A>G, p.Glu1979=, or p.E1979= entry was found in ATM_PVS1_1.5.pdf.txt; the file was searched for all three notations.
  • No observed RNA study demonstrating an aberrant transcript or exon-skipping event is available for this case.
Sources
cspec ↗vcep_atm_pvs1_1_5spliceai ↗
PS2 VCEPNot applicable: the ATM VCEP explicitly excludes PS2 for autosomal dominant and autosomal recessive disease. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP version 1.6 explicitly marks PS2 as not applicable for ATM-related autosomal dominant and autosomal recessive disease because informative de novo occurrences have not been observed and de novo evidence is not informative for the recessive condition.

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 version 1.6 lists PS2 as not applicable for ATM-related autosomal dominant and autosomal recessive disease.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP marks PM1 not applicable, and this variant is synonymous rather than a domain- or hotspot-based missense change. Details ▾Hide ▴
Reasoning

The governing ATM Version 1.6 framework marks PM1 as Not Applicable. This variant is synonymous (p.Glu1979=), not a missense change for which a critical functional domain or hotspot would provide PM1 evidence. No domain_tables entry was present in vcep_materials.json to expand the VCEP rule.

VCEP rule
ATM VCEP Version 1.6 PM1 applicability: Not Applicable.
Evidence considered
  • The ATM Version 1.6 framework lists PM1 as Not Applicable.
  • The normalized consequence is synonymous, p.Glu1979= / p.E1979=.
  • vcep_materials.json contains no domain_tables entry for ATM.
Sources
cspec ↗
PM4 N/ANot applicable: p.Glu1979= is synonymous and does not produce the stop-loss protein-length change required by the ATM PM4 rule. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP specification defines PM4 for stop-loss variants. NM_000051.4:c.5937A>G is synonymous and does not change protein length or remove a termination codon, so the PM4 stop-loss rule does not apply.

Rule
ClinGen HBOP ATM V1.6 PM4: use for stop-loss variants.
Evidence considered
  • The ATM VCEP PM4 rule specifies use for stop-loss variants.
  • The normalized protein consequence is synonymous, p.(Glu1979=), with no protein-length change or stop-loss event.
Still missing
  • No exact c.5937A>G, p.Glu1979=, or p.E1979= entry was found in ATM_PVS1_1.5.pdf.txt; the file was searched for all three notations and does not govern the ATM PM4 rule.
Sources
cspec ↗
PM5 N/ANot applicable: ATM PM5 is restricted to qualifying truncating variants upstream of p.Leu3048, whereas c.5937A>G is synonymous. Details ▾Hide ▴
Reasoning

The governing ATM framework defines PM5 for specific truncating variants upstream of p.Leu3048, with a supporting-strength pathway for qualifying truncating comparators; it is not the classic same-residue missense PM5 rule for this case. NM_000051.4:c.5937A>G is synonymous and does not meet that truncating-variant rule. The governing PM5 rule therefore makes PM5 not applicable.

Rule
ATM VCEP PM5: qualifying NMD-prone truncating variants upstream of p.Leu3048; not applicable to synonymous variants.
Evidence considered
  • The ATM VCEP PM5 rule applies to NMD-prone truncating variants with premature termination codons upstream of p.Leu3048, with the specified PVS1 prerequisites.
  • The variant is synonymous and has no premature termination codon.
  • The case PM5 assessment records classic same-residue missense PM5 as ineligible and identifies the governing mode as truncation_cutoff_gene_specific.
Sources
cspec ↗pm5_candidates
PM6 VCEPNot applicable: the ATM VCEP explicitly excludes PM6 for autosomal dominant and autosomal recessive disease. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP version 1.6 explicitly marks PM6 as not applicable for ATM-related autosomal dominant and autosomal recessive disease because informative de novo occurrences have not been observed and de novo evidence is not informative for the recessive condition.

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 version 1.6 lists PM6 as not applicable for ATM-related autosomal dominant and autosomal recessive disease.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP marks PP2 not applicable, and c.5937A>G is synonymous rather than missense. Details ▾Hide ▴
Reasoning

The governing ATM Version 1.6 framework explicitly marks PP2 as Not Applicable. In addition, PP2 is a missense-context criterion and this variant is synonymous, so no gene-level missense enrichment evidence can be assigned.

VCEP rule
ATM VCEP Version 1.6 PP2 applicability: Not Applicable.
Evidence considered
  • The ATM Version 1.6 framework lists PP2 as Not Applicable.
  • The normalized consequence is synonymous, p.Glu1979= / p.E1979=, so a missense-enrichment criterion does not apply.
Sources
cspec ↗
PP4 VCEPNot applicable: the ATM HBOP VCEP v1.6 explicitly designates PP4 as not applicable. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.6 explicitly marks PP4 as Not Applicable. No generic PP4 phenotype-specificity assessment is substituted because an applicable gene-specific framework governs this variant.

VCEP rule
Not Applicable under the ATM HBOP VCEP v1.6 specification.
Evidence considered
  • ATM HBOP VCEP v1.6 lists PP4 as Not Applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP excludes PP5, and ClinVar has zero expert-panel submissions for this exact variant. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.6 explicitly marks PP5 as Not Applicable. Independently, the exact ClinVar record has three ordinary single-submitter clinical laboratory assertions and zero expert-panel submissions; aggregate Benign/Likely benign labels therefore cannot trigger PP5 under the required exact-variant expert-panel rule.

VCEP rule
Not Applicable under the ATM HBOP VCEP v1.6 specification; under the requested rule, PP5 requires an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
  • ATM HBOP VCEP v1.6 lists PP5 as Not Applicable.
  • ClinVar exact-match audit reports three single-submitter clinical laboratory submissions and expert_panel_submissions = 0; no expert-panel Pathogenic or Likely pathogenic classification exists to support PP5.
Sources
cspec ↗clinvar ↗
BS2 VCEPNot applicable: ATM VCEP v1.6 excludes BS2 because ATM has incomplete penetrance. Details ▾Hide ▴
Reasoning

BS2 is not applicable under the ATM VCEP v1.6 specification, which explicitly states not to use BS2 because ATM has incomplete penetrance. Population absence or presence data cannot override that criterion-level applicability rule.

VCEP rule
ATM VCEP v1.6: BS2 is not applicable because ATM has incomplete penetrance.
Evidence considered
  • ATM VCEP version 1.6 states that BS2 should not be used because ATM has incomplete penetrance.
  • No homozygote or healthy-adult observation is needed to adjudicate BS2 because the governing specification makes the criterion not applicable.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP explicitly excludes BS4, so non-segregation cannot receive this criterion. Details ▾Hide ▴
Reasoning

The governing ClinGen HBOP ATM VCEP version 1.6 explicitly marks BS4 as not applicable for ATM. Therefore, absence of segregation cannot be used under BS4 in this adjudication, regardless of whether unaffected relatives were tested.

VCEP rule
Not applicable under the governing ATM VCEP specification.
Evidence considered
  • ClinGen HBOP ATM VCEP version 1.6 lists BS4 as not applicable.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP marks BP1 not applicable, and c.5937A>G is synonymous rather than missense. Details ▾Hide ▴
Reasoning

The governing ATM Version 1.6 framework explicitly marks BP1 as Not Applicable. BP1 would in any event concern a benign missense-context pattern, whereas this variant is synonymous.

VCEP rule
ATM VCEP Version 1.6 BP1 applicability: Not Applicable.
Evidence considered
  • The ATM Version 1.6 framework lists BP1 as Not Applicable.
  • The normalized consequence is synonymous, p.Glu1979= / p.E1979=.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP marks BP3 unavailable, and c.5937A>G is synonymous rather than an in-frame repeat-region insertion or deletion. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP specification marks BP3 as Not Applicable. In addition, BP3 is an in-frame insertion/deletion repeat-region criterion, whereas NM_000051.4:c.5937A>G is synonymous and has no protein-length change. BP3 therefore cannot be applied.

VCEP rule
ClinGen HBOP ATM V1.6: BP3 is Not Applicable.
Evidence considered
  • The ATM VCEP criteria payload marks BP3 as Not Applicable.
  • The normalized consequence is synonymous, with no in-frame insertion/deletion or protein-length change.
Still missing
  • No exact c.5937A>G, p.Glu1979=, or p.E1979= entry was found in ATM_PVS1_1.5.pdf.txt; the file was searched for all three notations and does not govern BP3.
Sources
cspec ↗
BP5 VCEPNot applicable: the ATM HBOP VCEP v1.6 explicitly designates BP5 as not applicable. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.6 explicitly marks BP5 as Not Applicable. No generic BP5 rule is substituted because an applicable gene-specific framework governs this variant.

VCEP rule
Not Applicable under the ATM HBOP VCEP v1.6 specification.
Evidence considered
  • ATM HBOP VCEP v1.6 lists BP5 as Not Applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP excludes BP6, and ClinVar has only ordinary laboratory assertions with zero expert-panel submissions. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP v1.6 explicitly marks BP6 as Not Applicable. The exact ClinVar record contains only ordinary single-submitter laboratory assertions (Benign or Likely benign), with zero expert-panel submissions, so those assertions cannot trigger BP6 under the required exact-variant expert-panel rule.

VCEP rule
Not Applicable under the ATM HBOP VCEP v1.6 specification; under the requested rule, BP6 requires an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
  • ATM HBOP VCEP v1.6 lists BP6 as Not Applicable.
  • ClinVar exact-match audit reports Benign/Likely benign laboratory submissions but expert_panel_submissions = 0; ordinary submissions and aggregate labels cannot trigger BP6.
Sources
cspec ↗clinvar ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.5937A>G
Protein (HGVS p.)
NP_000042.3:p.(Glu1979=)
GRCh38
chr11:108312429 A>G
GRCh37
chr11:108183156 A>G
Location and type
Exon 40 · synonymous
ClinVar
1750598

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

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -18 bp
0.247
SpliceAI acceptor gainat -336 bp
0.002
SpliceAI donor lossat +69 bp
0.157
SpliceAI donor gainat +295 bp
0.000
Pangolin splice lossmagnitude shown
-0.223
Pangolin splice gain
0.003

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SupportingMet at supporting: SpliceAI maximum delta 0.247 meets the ATM VCEP PP3 threshold of >=0.2 for predicted splice impact. Details ▾Hide ▴
Reasoning

The variant is synonymous (NM_000051.4:c.5937A>G; NP_000042.3:p.(Glu1979=)), so the applicable computational path is SpliceAI rather than REVEL. SpliceAI reports a maximum delta score of 0.247 (DS_AL 0.247), which meets the ATM VCEP v1.6 PP3 supporting threshold of >=0.2 for predicted splice impact in silent variants. The ATM VCEP PP3 rule is applied directly; the governing VCEP materials contain no per-variant pre-assigned PP3 code for c.5937A>G.

Rule
ATM VCEP v1.6 PP3 Supporting: Splicing—predicted impact via SpliceAI >=0.2 for silent variants.
Evidence considered
  • ATM VCEP version 1.6 specifies PP3 supporting for silent variants with predicted splice impact by SpliceAI >=0.2.
  • SpliceAI for NM_000051.4:c.5937A>G reports DS_AG 0.002, DS_AL 0.247, DS_DG 0.000, and DS_DL 0.157; the maximum delta is 0.247.
  • The searched ATM VCEP file Suppl_TableS1_PMID 40580951.xlsx contains the exact c.5937A>G row but does not pre-assign PP3 or BP4 and has NA predictor fields for this synonymous row.
Sources
cspec ↗spliceai ↗
BP7 SupportingMet at supporting: ATM VCEP v1.6 assigns BP7 supporting to synonymous variants, and this variant is c.5937A>G (p.Glu1979=). Details ▾Hide ▴
Reasoning

BP7 is in scope because the variant is synonymous. The ATM VCEP v1.6 directly specifies BP7 supporting for synonymous variants; its instructions also state that BP7 is not considered conflicting evidence against a body of evidence supporting a pathogenic splice defect. Therefore BP7 supporting applies from the synonymous consequence, independently of the SpliceAI PP3 result. No stronger BP7(RNA) level was assigned because no variant-specific RNA study demonstrating lack of an aberrant splice defect was identified.

Rule
ATM VCEP v1.6 BP7 Supporting: synonymous and deep intronic variants; BP7(RNA) separately requires observed lack of an aberrant RNA defect.
Evidence considered
  • ATM VCEP version 1.6 specifies BP7 supporting for synonymous variants and states that BP7 is not considered conflicting evidence against a body of evidence supporting a pathogenic splice defect.
  • NM_000051.4:c.5937A>G is annotated as synonymous, producing NP_000042.3:p.(Glu1979=).
  • No variant-specific RNA evidence demonstrating lack of an aberrant splice defect was present, so BP7(RNA) was not assigned at a stronger variable strength.
Sources
cspec ↗spliceai ↗
BP4 Not met: SpliceAI maximum delta 0.247 exceeds the ATM VCEP BP4 no-impact threshold of <=0.1. Details ▾Hide ▴
Reasoning

The variant is synonymous, so BP4 must use the SpliceAI path and cannot use REVEL. The ATM VCEP v1.6 BP4 supporting threshold for no predicted splice impact is SpliceAI <=0.1, but the observed maximum delta is 0.247. Therefore BP4 is not met; the applicable splice prediction instead reaches the PP3 threshold.

Rule
ATM VCEP v1.6 BP4 Supporting: Splicing—no predicted impact via SpliceAI <=0.1.
Evidence considered
  • ATM VCEP version 1.6 specifies BP4 supporting for silent/splicing variants with no predicted splice impact by SpliceAI <=0.1.
  • SpliceAI for NM_000051.4:c.5937A>G reports a maximum delta score of 0.247, above the BP4 cutoff.
  • REVEL was not evaluated because this is a synonymous variant and the governing one-path rule assigns synonymous variants to SpliceAI.
Sources
cspec ↗spliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.25).

6 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

Other recorded publications

  • Summaries for patients. Assessing the genetic risk for BRCA-related breast or ovarian cancer in women: recommendations from the U.S. Preventive Services Task Force.
    2014
    The paper addresses BRCA1 and BRCA2 cancer-risk assessment and does not report ATM c.5937A>G or provide variant-specific ATM case-control evidence.
    Does not name this variant
    PMID 24366402 ↗
    Quoted passage
    Mutations in 2 genes increase risk for breast and ovarian cancer: breast cancer susceptibility genes 1 and 2 (BRCA1 and BRCA2).

    What is the problem and what is known about it so far?

  • EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
    This consensus guideline discusses diagnosis and management of chronic adult ataxias, including general mention of ataxia-telangiectasia, but does not report ATM c.5937A>G or variant-specific case-control evidence.
    Does not name this variant
    PMID 24418350 ↗
    Quoted passage
    This guideline focuses on the heredodegenerative ataxias.

    Abstract, Background and objectives

  • Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.
    The paper addresses BRCA1/2 cancer-risk assessment, genetic counseling, and testing and does not report ATM c.5937A>G or variant-specific ATM case-control evidence.
    Does not name this variant
    PMID 31429903 ↗
  • PMID 31479213
    No paper-specific finding is recorded.
    PMID 31479213 ↗
  • ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
    The paper presents ACMG secondary-finding reporting recommendations and does not report ATM c.5937A>G or variant-specific clinical, case-control, or phenotype evidence.
    Does not name this variant
    PMID 34012068 ↗
  • 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 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.247 Open source ↗
ClinVar 2 Likely benign · 1 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 1750598)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.25).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

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.