0%
ATMc.9049C>TLikely benign
Print report
Variant interpretation report

ATM c.9049C>T, p.(Leu3017=)

NM_000051.4:c.9049C>T NP_000042.3:p.(Leu3017=) Synonymous · exon 63 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 v1.5. 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 (supporting): absent from gnomAD v4.1, an allele frequency of 0 at or below the 0.001% threshold.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

Met (supporting): SpliceAI maximum delta 0.023 is below the 0.1 benign splicing threshold.

BP7Supporting
BP7 · supporting

Met (supporting): the ATM VCEP assigns BP7 at supporting strength to synonymous variants like this one.

Recorded classification: Likely benign

Likely Benign: the VCEP Rule19 combination is met by two Benign-supporting criteria, BP4 and BP7, both 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
0.023 maximum delta

Recorded SpliceAI maximum delta score: 0.023. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions

3 Likely benign · 1 Uncertain significance · 1 Benign. ClinVar API review status: criteria provided, conflicting classifications.

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.

No listed criterion applied 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 v1.5, with the data and sources behind each one.

28 criteria with recorded statuses: 3 met · 5 not met · 6 not assessed · 14 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

Under the governing ATM VCEP v1.5 framework, this synonymous variant meets BP4_Supporting through the SpliceAI no-impact threshold and independently meets BP7_Supporting through the VCEP synonymous-variant rule; PP3 is not met.

Met · 3

PM2 SupportingMet (supporting): absent from gnomAD v4.1, an allele frequency of 0 at or below the 0.001% threshold. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 permits PM2_Supporting when the variant frequency is at or below 0.001% in gnomAD v4; it explicitly states that n=1 in a single subpopulation is sufficient. The variant is absent from gnomAD v4.1, consistent with an allele frequency of 0 and meeting the PM2_Supporting threshold.

Rule
Frequency <=0.001% in gnomAD v4 dataset; if n=1 in a single subpopulation, PM2_Supporting applies
Evidence considered
  • The governing ATM VCEP v1.5 specifies PM2_Supporting for frequency <=0.001% in gnomAD v4 and considers n=1 in a single subpopulation sufficient.
  • The variant NM_000051.4:c.9049C>T (ATM; GRCh38 chr11:108365386 C>T) was reported absent from gnomAD v4.1, providing no observed carriers and supporting a frequency of 0 in that dataset.
Sources
cspec ↗gnomad_v4 ↗
BP4 SupportingMet (supporting): SpliceAI maximum delta 0.023 is below the 0.1 benign splicing threshold. Details ▾Hide ▴
Reasoning

ATM c.9049C>T is a synonymous variant. The ATM VCEP BP4 splicing sub-path is applicable and is met because the SpliceAI maximum delta score is 0.023, below the VCEP benign threshold of 0.1. BP4 is applied once, for the splicing mechanism only. This is compatible with the VCEP instruction that BP4 may also be applied with BP7 for synonymous variants; BP7 is assigned separately from its VCEP synonymous-variant rule rather than by reusing the SpliceAI prediction.

Rule
ATM VCEP v1.5 BP4_Supporting, splicing sub-path: SpliceAI <=0.1; apply only once for the applicable mechanism.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies BP4_Supporting for no predicted splice impact at SpliceAI less than or equal to 0.1 and states that BP4 may also be applied with BP7 for synonymous variants.
  • SpliceAI maximum delta score is 0.023, meeting the VCEP BP4 splicing threshold.
Sources
cspec ↗spliceai ↗
BP7 SupportingMet (supporting): the ATM VCEP assigns BP7 at supporting strength to synonymous variants like this one. Details ▾Hide ▴
Reasoning

ATM c.9049C>T is a synonymous substitution (p.Leu3017=). The governing ATM VCEP directly specifies BP7 at supporting strength for synonymous variants. No RNA study is available to justify an RNA-based strength modification. BP7 is assigned from the VCEP synonymous-variant eligibility rule, not from the SpliceAI result used for BP4.

Rule
ATM VCEP v1.5 BP7_Supporting: use for synonymous variants; BP7(RNA) strength depends on observed lack of aberrant RNA defect and assay quality.
Evidence considered
  • Variant normalization identifies NM_000051.4:c.9049C>T as synonymous, NP_000042.3:p.(Leu3017=).
  • ClinGen HBOP ATM VCEP v1.5 directly specifies BP7_Supporting for synonymous variants and reserves BP7(RNA) variable strengths for observed lack of aberrant RNA defect.
Still missing
  • No variant-specific RNA assay is available to assess BP7(RNA) at a variable higher strength.
Sources
cspec ↗

Not met · 5 · evaluated, threshold not reached

PVS1 Not met: synonymous p.(Leu3017=) creates no premature stop codon, and SpliceAI max delta 0.023 predicts no splice impact. Details ▾Hide ▴
Reasoning

ATM c.9049C>T is annotated as the synonymous change p.(Leu3017=), not a null variant. It creates no premature termination codon and SpliceAI predicts no significant splice impact (maximum delta 0.023); therefore there is no predicted loss-of-function transcript, NMD substrate, or truncated protein to which the ATM PVS1 decision tree can apply.

Rule
ATM HBOP VCEP v1.5 PVS1 decision tree for null variants in ATM.
Evidence considered
  • The case normalization annotates NM_000051.4:c.9049C>T as NP_000042.3:p.(Leu3017=), a synonymous substitution.
  • The ATM HBOP VCEP PVS1 guide applies to null variants, including nonsense, frameshift, canonical ±1/2 splice, initiation-codon, and exon-deletion variants; this synonymous variant is not in a PVS1-eligible consequence class.
  • SpliceAI reported a maximum delta score of 0.023, below the ATM VCEP PP3 splicing threshold of 0.2 and consistent with no predicted splice impact.
Sources
cspec ↗vcep_atm_pvs1_1_5spliceai ↗
PM4 Not met: PM4 applies only to stop-loss variants, and this synonymous change does not alter the termination codon. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP specifies PM4 only for stop-loss variants. c.9049C>T is synonymous, p.(Leu3017=), and does not alter the termination codon or protein length.

Rule
ATM HBOP VCEP v1.5: PM4 applies to stop-loss variants.
Evidence considered
  • The case normalization annotates NM_000051.4:c.9049C>T as NP_000042.3:p.(Leu3017=), with no amino-acid or protein-length change.
  • ATM HBOP VCEP v1.5 specifies PM4 for stop-loss variants.
Sources
cspec ↗
PP3 Not met: SpliceAI maximum delta 0.023 falls below the 0.2 threshold required for PP3. Details ▾Hide ▴
Reasoning

ATM c.9049C>T is synonymous (p.Leu3017=). The governing ATM VCEP applies PP3_Supporting to silent variants only when SpliceAI is at least 0.2. The observed maximum delta score is 0.023, so the splice-impact PP3 threshold is not met. REVEL is unavailable and the VCEP supplementary table records REVEL as NA for this synonymous SNV; no independent calibrated protein-level PP3 evidence is available.

Rule
ATM VCEP v1.5 PP3_Supporting: SpliceAI >=0.2 for silent, missense/in-frame, and non-canonical intronic variants; missense REVEL >0.7333.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies PP3_Supporting for silent, missense/in-frame, and non-canonical intronic variants when SpliceAI is at least 0.2.
  • SpliceAI maximum delta score is 0.023 (DS_AG 0.023; all other reported delta scores are lower), below the VCEP PP3 threshold.
  • The ATM VCEP supplementary Table S1 row for c.9049C>T (L3017L; synonymous) reports REVEL as NA, so no REVEL result is available for the missense computational sub-path.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951
BA1 Not met: BA1 requires gnomAD allele frequency above 0.5%; the variant is absent from gnomAD v4.1. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 BA1 rule requires a gnomAD v4 grpmax filtering allele frequency greater than 0.5%. The variant is absent from gnomAD v4.1, so this threshold is not met.

Rule
Grpmax Filtering AF >0.5% in gnomAD v4 dataset
Evidence considered
  • The governing ATM VCEP v1.5 specifies BA1 for grpmax filtering AF >0.5% in gnomAD v4.
  • The variant NM_000051.4:c.9049C>T (ATM; GRCh38 chr11:108365386 C>T) was reported absent from gnomAD v4.1; therefore no population frequency reaches the BA1 threshold.
Sources
cspec ↗gnomad_v4 ↗
BS1 Not met: BS1 requires gnomAD allele frequency above 0.05%; the variant is absent from gnomAD v4.1. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 BS1 rule requires a gnomAD v4 grpmax filtering allele frequency greater than 0.05%. The variant is absent from gnomAD v4.1, so this threshold is not met.

Rule
Grpmax Filtering AF >0.05% in gnomAD v4 dataset
Evidence considered
  • The governing ATM VCEP v1.5 specifies BS1 for grpmax filtering AF >0.05% in gnomAD v4.
  • The variant NM_000051.4:c.9049C>T (ATM; GRCh38 chr11:108365386 C>T) was reported absent from gnomAD v4.1; therefore no population frequency reaches the BS1 threshold.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 6 · no assessment recorded

PS3 Not assessed: no variant-specific functional assay result (kinase activity or rescue) was available. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.5 specification requires variant-specific functional evidence and states that PS3 is not used at Strong; Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity, while Supporting requires failure to rescue an ATM-specific feature. The case bundle contains no result showing that ATM c.9049C>T (p.Leu3017=) was tested in an approved assay, and no variant-specific ATM kinase-activity or other ATM-specific readout is available. Therefore PS3 cannot be assigned.

Rule
ATM VCEP v1.5 PS3: do not use Strong; Supporting requires failure to rescue an ATM-specific feature, and Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies PS3 Supporting for failure to rescue an ATM-specific feature alone, PS3 Moderate for failure to rescue both an ATM-specific feature and radiosensitivity, and prohibits PS3 Strong.
  • The VCEP functional-assay table is a methodology and strength-calibration document, not a per-variant results table; it requires confirmation that the assessed variant was actually tested in one of the named assays.
  • The consolidated case-evidence bundle provides no variant-specific functional assay result for ATM c.9049C>T (p.Leu3017=).
Still missing
  • Confirm whether NM_000051.4:c.9049C>T was experimentally tested in an assay accepted by the ATM VCEP.
  • Obtain the variant-specific ATM functional readout, including appropriate wild-type and ATM-null controls.
  • For PS3_Moderate, obtain both an ATM-specific feature result and a radiosensitivity result and assess their concordance.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4 Not assessed: no variant-specific case-control data (p-value <=0.05, OR/HR/RR >=2) were available. Details ▾Hide ▴
Reasoning

ATM VCEP v1.5 permits PS4 at Strong only for case-control evidence with p-value ≤0.05 and OR, HR, or RR ≥2 (or lower 95% CI ≥1.5). No variant-specific case-control data for ATM c.9049C>T (p.Leu3017=) were identified in the supplied evidence.

Rule
ATM VCEP v1.5 PS4: case-control studies; p-value ≤0.05 and OR, HR, or RR ≥2, or lower 95% CI ≥1.5.
Evidence considered
  • The ATM VCEP PS4 rule requires a case-control study with p-value ≤0.05 and OR, HR, or RR ≥2, or a lower 95% confidence bound ≥1.5.
  • PMID:18163131 discusses ATM at the gene level; its extracted review states that c.9049C>T/p.(L3017=) is not explicitly mentioned.
  • PMID:24366376 and PMID:31429903 do not provide variant-specific ATM c.9049C>T case-control data.
Still missing
  • A variant-specific case-control study reporting the effect estimate, 95% confidence interval, and p-value is required.
Sources
cspec ↗PMID:18163131 ↗PMID:24366376 ↗PMID:31429903 ↗
PM3 Not assessed: no affected A-T proband, second ATM variant, or phase information was available. Details ▾Hide ▴
Reasoning

The applicable ClinGen HBOP ATM VCEP v1.5 PM3 rule is the Ataxia-Telangiectasia points-based framework, requiring affected-proband evidence with the variant homozygous or with a second ATM variant, with phase and the second variant's pathogenicity considered. The case-evidence bundle contains no affected A-T proband observation, no documented second pathogenic/likely pathogenic ATM variant, and no phase, cis/trans, or parental/offspring information for NM_000051.4:c.9049C>T. Therefore no PM3 points can be assigned.

Rule
ATM VCEP v1.5 PM3: assign points from qualifying unrelated A-T probands; PM3 Supporting = 1 point, Moderate = 2 points, Strong = 4 points, Very Strong >= 8 points. No qualifying observations are documented here.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies PM3 for ATM-related ataxia-telangiectasia using points per unrelated A-T proband, with separate weights for confirmed trans, phase unknown, an unidentified/VUS second variant, or homozygosity.
  • The consolidated case-evidence bundle provides no affected A-T proband, compound-heterozygous observation, homozygous observation, second pathogenic/likely pathogenic ATM variant, or documented cis/trans phase for c.9049C>T.
Still missing
  • Affected-proband observations for this variant are not available.
  • No pathogenic or likely pathogenic second ATM variant is documented in the case.
  • No parental testing or other phase evidence establishing trans or cis is available.
  • No homozygous A-T case or qualifying phenotype/laboratory details are available.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 Not assessed: no family segregation, affected-relative genotype, or phase data for this variant were available. Details ▾Hide ▴
Reasoning

PP1 is applicable only to the autosomal recessive ATM disease context under the VCEP, with affected relatives required to have both variants identified in the proband. The case bundle contains no proband-level family segregation data, affected-relative genotypes, parental testing, phase information, or meiosis count that can establish segregation of this synonymous variant. The available literature extracts do not report this variant or relevant family segregation evidence.

Rule
AR condition: Supporting for segregation in 1 affected relative, Moderate for 2 affected relatives, and Strong for at least 3 affected relatives; affected relatives must have both variants identified in the proband.
Evidence considered
  • ATM VCEP v1.5 states for PP1: 'AR Condition: Affected relatives must have both variants identified in proband.'
  • The case bundle provides no variant-specific proband, parental, affected-relative, phase, or segregation observations for NM_000051.4:c.9049C>T.
Still missing
  • Documented affected relatives with phenotype consistency and testing results
  • Confirmation that affected relatives carry both ATM variants identified in the proband
  • Parental testing/phase information and informative meioses
  • Variant-specific segregation report or publication
Sources
cspec ↗
BS3 Not assessed: no variant-specific rescue assay result (ATM-specific function or radiosensitivity) was available. Details ▾Hide ▴
Reasoning

The ATM VCEP v1.5 specification requires variant-specific functional evidence and defines BS3 Supporting when a variant rescues either an ATM-specific feature or radiosensitivity, and BS3 Moderate when it rescues both. The case bundle contains no result showing that ATM c.9049C>T (p.Leu3017=) was tested in an accepted assay and no variant-specific rescue readout is available. Therefore BS3 cannot be assigned.

Rule
ATM VCEP v1.5 BS3: Supporting requires rescue of either an ATM-specific feature or radiosensitivity; Moderate requires rescue of both.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies BS3 Supporting for rescue of either an ATM-specific feature or radiosensitivity and BS3 Moderate for rescue of both.
  • The VCEP functional-assay table is a methodology and strength-calibration document, not a per-variant results table; the assessed variant must be confirmed in the underlying assay publication.
  • The consolidated case-evidence bundle provides no variant-specific functional assay result for ATM c.9049C>T (p.Leu3017=).
Still missing
  • Confirm whether NM_000051.4:c.9049C>T was experimentally tested in an assay accepted by the ATM VCEP.
  • Obtain the variant-specific rescue result with validated wild-type, disease-control, and ATM-null controls.
  • For BS3_Moderate, obtain concordant rescue of both an ATM-specific feature and radiosensitivity; for BS3_Supporting, at least one qualifying rescue readout is needed.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP2 Not assessed: no unaffected biallelic individual, in-trans pathogenic variant, or phase information was available. Details ▾Hide ▴
Reasoning

The applicable ClinGen HBOP ATM VCEP v1.5 BP2 rule is the points-based co-occurrence framework for unaffected non-A-T individuals carrying the variant with a pathogenic or likely pathogenic ATM variant in trans. The case-evidence bundle contains no unaffected biallelic individual, no documented pathogenic/likely pathogenic ATM variant in trans, and no phase or family information establishing cis/trans co-occurrence. Therefore no BP2 points can be assigned.

Rule
ATM VCEP v1.5 BP2: assign -1 point for Supporting, -2 points for Moderate, and <= -4 points for Strong based on qualifying unaffected co-occurrence observations. No qualifying observations are documented here.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies BP2 as negative points from unaffected non-A-T individuals carrying the variant with a pathogenic or likely pathogenic ATM variant in trans, with weights based on confirmed versus unknown phase and laboratory versus database setting.
  • The consolidated case-evidence bundle provides no unaffected biallelic individual, no qualifying co-occurrence with a pathogenic/likely pathogenic ATM variant, and no documented cis/trans phase for c.9049C>T.
Still missing
  • Unaffected non-A-T individual observations carrying this variant are not available.
  • No co-occurring pathogenic or likely pathogenic ATM variant is documented.
  • No parental testing or other phase evidence establishing trans or cis is available.
  • No qualifying laboratory-setting or database-setting co-occurrence observation is available.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: the variant is synonymous rather than missense, and no splice event matching a known pathogenic reference variant is documented. Details ▾Hide ▴
Reasoning

The variant is synonymous, NM_000051.4:c.9049C>T, p.(Leu3017=), not a missense substitution. The ATM VCEP PS1 missense pathway therefore does not apply. The alternative ATM PS1 splicing pathway requires a demonstrated or predicted splice event matching a known P/LP reference variant; SpliceAI predicts no significant splice impact (maximum delta score 0.023), and no matching pathogenic splice reference is documented.

Rule
ATM VCEP PS1 is for missense changes when splicing is ruled out; the splicing pathway requires a matching splice event and an established P/LP reference variant.
Evidence considered
  • The normalized consequence is synonymous: NM_000051.4:c.9049C>T produces NP_000042.3:p.(Leu3017=).
  • The ATM VCEP specifies PS1 for missense changes when splicing is ruled out and provides a separate splicing table requiring comparable splice predictions or observations against a known pathogenic or likely pathogenic variant.
  • SpliceAI reports no significant predicted splice impact for this variant, with maximum delta score 0.023.
Sources
cspec ↗vcep_atm_ps1_1_5spliceai ↗
PS2 VCEPNot applicable: the ATM VCEP specifies PS2 is not used for ATM disease, so no de novo evidence is assigned. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP version 1.5 specifies that PS2 is not applicable for either autosomal dominant or autosomal recessive ATM disease because informative de novo occurrences have not been observed and de novo autosomal recessive conditions are unlikely to be informed by phase. No de novo evidence is therefore assigned.

VCEP rule
Do not use for AD or AR disease.
Evidence considered
  • ATM VCEP v1.5 states: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.'
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP has no domain-table residue list, and the variant is synonymous rather than missense. Details ▾Hide ▴
Reasoning

The ATM VCEP framework marks PM1 as Not Applicable. The vcep_materials.json domain_tables object has no ATM entry, so there is no authoritative VCEP domain-table residue list to apply. In addition, this variant is synonymous and does not establish a missense alteration in a critical functional domain or hotspot.

VCEP rule
ATM VCEP PM1: Not Applicable.
Evidence considered
  • The governing ClinGen HBOP ATM VCEP Version 1.5 marks PM1 as Not Applicable.
  • The case vcep_materials.json domain_tables object is empty for ATM; no approved critical-domain entry is available for residue 3017.
  • The variant is synonymous, p.(Leu3017=), so it does not produce an amino-acid substitution for missense-domain evidence.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 targets truncating variants upstream of p.Arg3047; this synonymous change creates no premature stop codon. Details ▾Hide ▴
Reasoning

The ATM-specific PM5 rule applies to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, with a corresponding splice-variant pathway for NMD-prone splice defects. NM_000051.4:c.9049C>T is synonymous and creates no premature termination codon or documented splice defect, so PM5 is not applicable.

Rule
ATM VCEP PM5: apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047; splice variants require an equivalent NMD-prone splice-defect assessment.
Evidence considered
  • The ATM VCEP PM5 rule is limited to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, and qualifying NMD-prone splice variants.
  • The case PM5 candidate assessment identifies the gene-specific PM5 mode as a truncation-cutoff rule and marks this synonymous variant as ineligible for classic PM5 searching.
  • The variant is synonymous, p.(Leu3017=), with no premature termination codon and no documented splice defect.
Sources
cspec ↗pm5_candidates
PM6 VCEPNot applicable: the ATM VCEP explicitly lists PM6 as not applicable. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP version 1.5 explicitly lists PM6 as not applicable. No non-confirmed de novo evidence is assigned.

VCEP rule
Not applicable for ATM under the VCEP specification.
Evidence considered
  • ATM VCEP v1.5 marks PM6 as 'Not applicable'.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP marks PP2 as not applicable, and the variant is synonymous. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly marks PP2 as Not Applicable because ATM does not have a defined low rate of benign missense variation. The current variant is also synonymous rather than missense.

VCEP rule
ATM VCEP PP2: Not Applicable; ATM does not have a defined low rate of benign missense variation.
Evidence considered
  • The governing ATM VCEP states: do not use PP2 because ATM does not have a defined low rate of benign missense variation.
  • The normalized variant consequence is synonymous, p.(Leu3017=), not missense.
Sources
cspec ↗
PP4 VCEPNot applicable: the ATM VCEP designates PP4 as not applicable. Details ▾Hide ▴
Reasoning

PP4 is designated Not Applicable by the governing ATM VCEP v1.5 specification.

VCEP rule
ATM VCEP v1.5: PP4 Not Applicable.
Evidence considered
  • The governing ATM VCEP v1.5 specification marks PP4 as Not Applicable.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP designates PP5 as not applicable, and no expert-panel ClinVar submission exists. Details ▾Hide ▴
Reasoning

PP5 is designated Not Applicable by the governing ATM VCEP v1.5 specification. Independently, the exact-variant ClinVar record has no expert-panel submission; its reported Likely benign, Benign, and VUS assertions are single-submitter laboratory assertions and cannot trigger PP5.

VCEP rule
ATM VCEP v1.5: PP5 Not Applicable; when considered, PP5 requires an exact-variant ClinVar expert-panel Pathogenic/Likely pathogenic classification.
Evidence considered
  • The governing ATM VCEP v1.5 specification marks PP5 as Not Applicable.
  • ClinVar submission audit for the exact variant reports zero expert-panel submissions; all five submissions are non-expert single-submitter laboratory assertions.
Sources
cspec ↗clinvar ↗
BS2 VCEPNot applicable: the ATM VCEP marks BS2 as not applicable. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP v1.5 marks BS2 as not applicable. No BS2 assessment is made from the available population data.

Evidence considered
  • The governing ATM VCEP v1.5 lists BS2 as not applicable.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP specifies BS4 as not applicable for this disease context. Details ▾Hide ▴
Reasoning

The ClinGen HBOP ATM VCEP version 1.5 specifies BS4 as not applicable. It states that informative instances of lack of co-segregation in A-T families are too rare to receive weight at this time; for autosomal dominant ATM-related cancer predisposition, co-segregation analysis in this lower-penetrance context can generate false-positive results.

VCEP rule
Not applicable for ATM under the VCEP specification.
Evidence considered
  • ATM VCEP v1.5 marks BS4 as 'Not applicable' and states: 'Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time.'
  • ATM VCEP v1.5 cautions that co-segregation analysis in lower-penetrance genes can lead to false-positive results.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP marks BP1 as not applicable because missense pathogenic variants are known. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly marks BP1 as Not Applicable because missense pathogenic variants are known for ATM. The current variant is synonymous rather than missense, so the generic BP1 scenario does not apply.

VCEP rule
ATM VCEP BP1: Not Applicable; missense pathogenic variants are known for ATM.
Evidence considered
  • The governing ATM VCEP states: do not use BP1 because missense pathogenic variants are known for ATM.
  • The normalized variant consequence is synonymous, p.(Leu3017=), not missense.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP designates BP3 as not applicable. Details ▾Hide ▴
Reasoning

BP3 is designated Not Applicable by the ATM HBOP VCEP v1.5 framework. Repeat-region assessment cannot override this gene-specific inapplicability.

VCEP rule
ATM HBOP VCEP v1.5: BP3 is not applicable.
Evidence considered
  • The ATM HBOP VCEP v1.5 criteria list BP3 as Not Applicable.
Sources
cspec ↗
BP5 VCEPNot applicable: the ATM VCEP designates BP5 as not applicable. Details ▾Hide ▴
Reasoning

BP5 is designated Not Applicable by the governing ATM VCEP v1.5 specification.

VCEP rule
ATM VCEP v1.5: BP5 Not Applicable.
Evidence considered
  • The governing ATM VCEP v1.5 specification marks BP5 as Not Applicable.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP designates BP6 as not applicable, and no expert-panel ClinVar submission exists. Details ▾Hide ▴
Reasoning

BP6 is designated Not Applicable by the governing ATM VCEP v1.5 specification. Independently, the exact-variant ClinVar record has no expert-panel submission; its benign and likely benign assertions are ordinary laboratory submissions and cannot trigger BP6.

VCEP rule
ATM VCEP v1.5: BP6 Not Applicable; when considered, BP6 requires an exact-variant ClinVar expert-panel Benign/Likely benign classification.
Evidence considered
  • The governing ATM VCEP v1.5 specification marks BP6 as Not Applicable.
  • ClinVar submission audit for the exact variant reports zero expert-panel submissions; benign and likely benign assertions are non-expert single-submitter laboratory assertions.
Sources
cspec ↗clinvar ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.9049C>T
Protein (HGVS p.)
NP_000042.3:p.(Leu3017=)
GRCh38
chr11:108365386 C>T
GRCh37
chr11:108236113 C>T
Location and type
Exon 63 · synonymous
ClinVar
231160

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 -61 bp
0.008
SpliceAI acceptor gainat +330 bp
0.023
SpliceAI donor lossat +116 bp
0.011
SpliceAI donor gainat +396 bp
0.002
Pangolin splice lossmagnitude shown
-0.041
Pangolin splice gain
0.001

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMet (supporting): SpliceAI maximum delta 0.023 is below the 0.1 benign splicing threshold. Details ▾Hide ▴
Reasoning

ATM c.9049C>T is a synonymous variant. The ATM VCEP BP4 splicing sub-path is applicable and is met because the SpliceAI maximum delta score is 0.023, below the VCEP benign threshold of 0.1. BP4 is applied once, for the splicing mechanism only. This is compatible with the VCEP instruction that BP4 may also be applied with BP7 for synonymous variants; BP7 is assigned separately from its VCEP synonymous-variant rule rather than by reusing the SpliceAI prediction.

Rule
ATM VCEP v1.5 BP4_Supporting, splicing sub-path: SpliceAI <=0.1; apply only once for the applicable mechanism.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies BP4_Supporting for no predicted splice impact at SpliceAI less than or equal to 0.1 and states that BP4 may also be applied with BP7 for synonymous variants.
  • SpliceAI maximum delta score is 0.023, meeting the VCEP BP4 splicing threshold.
Sources
cspec ↗spliceai ↗
BP7 SupportingMet (supporting): the ATM VCEP assigns BP7 at supporting strength to synonymous variants like this one. Details ▾Hide ▴
Reasoning

ATM c.9049C>T is a synonymous substitution (p.Leu3017=). The governing ATM VCEP directly specifies BP7 at supporting strength for synonymous variants. No RNA study is available to justify an RNA-based strength modification. BP7 is assigned from the VCEP synonymous-variant eligibility rule, not from the SpliceAI result used for BP4.

Rule
ATM VCEP v1.5 BP7_Supporting: use for synonymous variants; BP7(RNA) strength depends on observed lack of aberrant RNA defect and assay quality.
Evidence considered
  • Variant normalization identifies NM_000051.4:c.9049C>T as synonymous, NP_000042.3:p.(Leu3017=).
  • ClinGen HBOP ATM VCEP v1.5 directly specifies BP7_Supporting for synonymous variants and reserves BP7(RNA) variable strengths for observed lack of aberrant RNA defect.
Still missing
  • No variant-specific RNA assay is available to assess BP7(RNA) at a variable higher strength.
Sources
cspec ↗
PP3 Not met: SpliceAI maximum delta 0.023 falls below the 0.2 threshold required for PP3. Details ▾Hide ▴
Reasoning

ATM c.9049C>T is synonymous (p.Leu3017=). The governing ATM VCEP applies PP3_Supporting to silent variants only when SpliceAI is at least 0.2. The observed maximum delta score is 0.023, so the splice-impact PP3 threshold is not met. REVEL is unavailable and the VCEP supplementary table records REVEL as NA for this synonymous SNV; no independent calibrated protein-level PP3 evidence is available.

Rule
ATM VCEP v1.5 PP3_Supporting: SpliceAI >=0.2 for silent, missense/in-frame, and non-canonical intronic variants; missense REVEL >0.7333.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.5 specifies PP3_Supporting for silent, missense/in-frame, and non-canonical intronic variants when SpliceAI is at least 0.2.
  • SpliceAI maximum delta score is 0.023 (DS_AG 0.023; all other reported delta scores are lower), below the VCEP PP3 threshold.
  • The ATM VCEP supplementary Table S1 row for c.9049C>T (L3017L; synonymous) reports REVEL as NA, so no REVEL result is available for the missense computational sub-path.
Sources
cspec ↗spliceai ↗vcep_suppl_tables1_pmid_40580951

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

7 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • 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 ↗
  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    The paper identifies ATM as a rare moderate-penetrance breast cancer susceptibility gene, but it does not report the exact synonymous variant c.9049C>T (NP_000042.3:p.(L3017=)) or a variant-specific case-control estimate for it.
    Does not name this variant
    PMID 18163131 ↗
    Quoted passage
    In CHEK2, ATM, BRIP1 and PALB2, most of the disease-causing mutations result in premature protein truncation or nonsense-mediated RNA decay through nonsense codons or translational frameshifts. A small proportion is likely to be rare missense variants that disrupt critical functions.

    Rare moderate-penetrance breast cancer susceptibility genes, page 18

  • Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
    Moyer VA et al. · 2014
    This BRCA1/BRCA2 risk-assessment paper does not mention ATM or ATM c.9049C>T (NP_000042.3:p.(L3017=)) and provides no variant-specific case-control evidence.
    Does not name this variant
    PMID 24366376 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    No paper-specific finding is recorded.
    PMID 26389258 ↗
  • Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.
    The paper does not report ATM c.9049C>T or NP_000042.3:p.(L3017=) and provides no variant-specific clinical or case-control evidence; ATM appears only as an example of a moderate-penetrance gene in discussion of multigene testing.
    Does not name this variant
    PMID 31429903 ↗
    Quoted passage
    Several comments requested changes to the recommendation related to newer genetic testing options. This includes the use of multigene panels, expanding the recommendation to include other gene mutations linked to increased risk of cancer (eg, TP53, ATM, PALB2), and the use of direct-to-consumer testing. The USPSTF acknowledges that there is increasing access to multigene panels; however, the clinical significance of identifying pathogenic variants in multigene panels requires further investigation. The evidence is currently limited on other moderate penetrance genes, given their relatively low incidence in the population. The USPSTF’s recommendation focuses on BRCA1/2 mutations because they are more prevalent and the findings are clinically actionable.

    Response to Public Comment

  • ATM-Related Cancer Predisposition.
    No paper-specific finding is recorded.
    PMID 42258614 ↗
  • 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 0.023 Open source ↗
ClinVar 3 Likely benign · 1 Uncertain significance · 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 (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 231160)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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.