0%
ATMc.3137T>CLikely pathogenic
Print report
Variant interpretation report

ATM c.3137T>C, p.(Leu1046Pro)

NM_000051.4:c.3137T>C NP_000042.3:p.(Leu1046Pro) View identifiers
Classification
Likely pathogenic

Variant description:

No variant summary was recorded for this case.

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

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

In plain language

Gene-level background from the recorded interpretation.

About ATM

No gene-level summary was recorded for this case.

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 v1.5.0. 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: 0
Pathogenic criteria applied · 1
PP3Supporting
PP3 · supporting

In silico evidence supports a deleterious missense effect: the REVEL score is 0.854, which is above the ATM PP3 threshold of 0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

ATM HBOP CSPEC/VCEP v1.5.0 cspec_ruleset final-classification framework from final_classification_framework.json; Rule19 applies.

02The sources

Evidence at a glance

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

gnomAD v4.1
gnomAD v2.1
Population frequency
3 / 1,613,832 alleles

gnomAD v4.1: 3 / 1,613,832 alleles. Recorded AF 1.85893e-06. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · PP3 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

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 v1.5.0, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 5 not met · 6 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

The ATM c.3137T>C (p.Leu1046Pro) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles; 0 homozygotes), with the highest observed frequency in the South Asian population at 2.19587e-05 (2/91080 alleles; 0 homozygotes).

In silico evidence supports a deleterious missense effect, with REVEL 0.854 exceeding the ATM PP3 threshold of 0.7333, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).

Met · 1

PP3 SupportingIn silico evidence supports a deleterious missense effect: the REVEL score is 0.854, which is above the ATM PP3 threshold of 0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. Details ▾Hide ▴
Rule
ATM PP3_Supporting for missense variants: REVEL >0.7333.
Evidence considered
  • REVEL 0.854
  • ATM PP3 threshold >0.7333
  • SpliceAI max delta score 0.01
Sources
prefetch.jsonevidence.jsoncase_summary.json

Not met · 5 · evaluated, threshold not reached

PS1 No pathogenic or likely pathogenic ATM variant producing the same amino acid change was identified in the available disease databases or ATM PS1 materials, so PS1 is not met. Details ▾Hide ▴
Rule
ATM PS1 requires a pathogenic/likely pathogenic reference variant with the same amino acid change after splicing is ruled out.
Evidence considered
  • ClinVar shows no result for NM_000051.4:c.3137T>C
  • ATM PS1 guidance was reviewed
  • No same amino acid pathogenic reference was identified
Still missing
  • No same-amino-acid pathogenic reference variant was identified in the available sources.
Sources
evidence.jsonvcep_materials.json
PM2 This variant is absent from gnomAD v2.1 and is very rare in gnomAD v4.1 overall (AF 1.85893e-06; 3/1613832 alleles), but the highest observed South Asian frequency is 2.19587e-05 (0.00220%; 2/91080), which is above the ATM PM2_Supporting threshold of 0.001%, so PM2 was not applied. Details ▾Hide ▴
Rule
ATM PM2_Supporting: frequency ≤0.001% in gnomAD v4 dataset; single-allele observation in one subpopulation may still qualify.
Evidence considered
  • gnomAD v2.1 absent
  • gnomAD v4.1 total AF 1.8589295540056215e-06
  • South Asian AF 2.1958717610891526e-05 with 2 alleles
  • 0 homozygotes observed
Sources
case_summary.jsonevidence.json
BA1 The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), which is below the ATM BA1 threshold of 0.5%, so BA1 is not met. Details ▾Hide ▴
Rule
ATM BA1: grpmax filtering AF >0.5% in gnomAD v4.
Evidence considered
  • gnomAD v4.1 grpmax FAF 3.65e-06
Sources
case_summary.jsonevidence.json
BS1 The gnomAD v4.1 grpmax filtering allele frequency is 3.65e-06 (0.000365%), which is below the ATM BS1 threshold of 0.05%, so BS1 is not met. Details ▾Hide ▴
Rule
ATM BS1: grpmax filtering AF >0.05% in gnomAD v4.
Evidence considered
  • gnomAD v4.1 grpmax FAF 3.65e-06
Sources
case_summary.jsonevidence.json
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splicing threshold of 0.1, but the REVEL score is 0.854, which is above the ATM BP4 missense threshold of 0.249, so BP4 is not met. Details ▾Hide ▴
Rule
ATM BP4_Supporting for missense variants: REVEL ≤0.249; for splicing: SpliceAI ≤0.1.
Evidence considered
  • REVEL 0.854
  • SpliceAI max delta score 0.01
  • ATM BP4 missense threshold ≤0.249
Sources
prefetch.jsonevidence.jsoncase_summary.json

Not assessed · 6 · no assessment recorded

PS3 No variant-specific ATM functional study was identified showing failure to rescue both an ATM-specific function and radiosensitivity, so PS3 was not assessed. Details ▾Hide ▴
Rule
ATM PS3_Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity; PS3_Supporting requires failure to rescue an ATM-specific feature.
Evidence considered
  • ATM CSPEC PS3 requires failure to rescue ATM-specific function and/or radiosensitivity
  • No exact match for c.3137T>C or p.(Leu1046Pro) was identified in the ATM kinase activity or ATM radiosensitivity supplementary tables
Still missing
  • No qualifying variant-specific functional rescue/failure-to-rescue assay was identified.
Sources
vcep_materials.jsonclingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx
PS4 No case-control data or statistically significant enrichment data for this variant were identified, so PS4 was not assessed. Details ▾Hide ▴
Rule
ATM PS4 requires p-value ≤0.05 and risk estimate ≥2 or lower 95% CI ≥1.5.
Evidence considered
  • ATM PS4 requires case-control evidence
  • No PMIDs or case-control studies were retrieved
Still missing
  • No case-control study or enrichment data were identified.
Sources
case_summary.jsonliterature_pass.json
PM3 No observations of this variant in trans with a pathogenic ATM variant in individuals with ataxia-telangiectasia were identified, so PM3 was not assessed. Details ▾Hide ▴
Rule
ATM PM3 uses a point-based trans observation system in A-T probands.
Evidence considered
  • ATM PM3 requires weighted proband evidence for recessive disease
  • No PMIDs or case-level phase data were retrieved
Still missing
  • No proband-level phase or trans data were identified.
Sources
vcep_materials.jsonliterature_pass.json
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
ATM PP1 for the recessive condition requires segregation in affected relatives.
Evidence considered
  • No PMIDs retrieved
  • No segregation observations available
Still missing
  • No informative family segregation data were identified.
Sources
literature_pass.jsoncase_summary.json
BS3 No variant-specific ATM functional study was identified showing rescue of ATM-specific function or radiosensitivity, so BS3 was not assessed. Details ▾Hide ▴
Rule
ATM BS3_Moderate requires rescue of both an ATM-specific feature and radiosensitivity; BS3_Supporting requires rescue of either one.
Evidence considered
  • ATM BS3 requires functional rescue evidence
  • No exact match for c.3137T>C or p.(Leu1046Pro) was identified in the ATM kinase activity or ATM radiosensitivity supplementary tables
Still missing
  • No qualifying variant-specific rescue assay was identified.
Sources
vcep_materials.jsonclingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx
BP2 No co-occurrence data were identified showing this variant in trans with a pathogenic ATM variant in an unaffected non-ataxia-telangiectasia setting, so BP2 was not assessed. Details ▾Hide ▴
Rule
ATM BP2 uses weighted co-occurrence evidence in unaffected non-A-T individuals.
Evidence considered
  • ATM BP2 uses a point-based co-occurrence framework
  • No proband-level co-occurrence evidence was retrieved
Still missing
  • No informative co-occurrence and phase data were identified.
Sources
vcep_materials.jsonliterature_pass.json
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant and does not create a premature termination codon or affect a canonical ±1,2 splice site, so the ATM PVS1 framework does not support applying PVS1. Details ▾Hide ▴
Rule
ATM PVS1 decision tree applies to null/splice categories, not this missense change.
Evidence considered
  • NM_000051.4:c.3137T>C corresponds to p.(Leu1046Pro)
  • pvs1_variant_assessment.json states this variant is outside the default generic PVS1 null-variant buckets
  • ATM has a PVS1 framework, but this variant class is not eligible for it
Sources
pvs1_variant_assessment.jsonpvs1_gene_context.jsonvcep_materials.json
PS2 N/AThe ATM CSPEC marks PS2 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists PS2 as not applicable
Sources
case_summary.json
PM1 N/AThe ATM CSPEC marks PM1 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists PM1 as not applicable
Sources
case_summary.json
PM4 N/AThis is not a stop-loss variant, so PM4 is not applicable. Details ▾Hide ▴
Rule
ATM PM4 is specified for stop-loss variants.
Evidence considered
  • Variant type is missense p.(Leu1046Pro)
Sources
case_summary.json
PM5 N/AThe ATM PM5 specification is limited to truncating or qualifying splice variants upstream of p.Arg3047, so it does not apply to this missense variant. Details ▾Hide ▴
Rule
ATM PM5_Supporting applies to truncating or qualifying splice variants upstream of p.Arg3047.
Evidence considered
  • Variant type is missense p.(Leu1046Pro)
  • ATM PM5 specification in CSPEC is restricted to truncating/splice contexts
Sources
case_summary.json
PM6 N/AThe ATM CSPEC marks PM6 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists PM6 as not applicable
Sources
case_summary.json
PP2 N/AThe ATM CSPEC marks PP2 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists PP2 as not applicable
Sources
case_summary.json
PP4 N/AThe ATM CSPEC marks PP4 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists PP4 as not applicable
Sources
case_summary.json
PP5 N/AThe ATM CSPEC marks PP5 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists PP5 as not applicable
Sources
case_summary.json
BS2 N/AThe ATM CSPEC marks BS2 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists BS2 as not applicable
Sources
case_summary.json
BS4 N/AThe ATM CSPEC marks BS4 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists BS4 as not applicable
Sources
case_summary.json
BP1 N/AThe ATM CSPEC marks BP1 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists BP1 as not applicable
Sources
case_summary.json
BP3 N/AThe ATM CSPEC marks BP3 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists BP3 as not applicable
Sources
case_summary.json
BP5 N/AThe ATM CSPEC marks BP5 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists BP5 as not applicable
Sources
case_summary.json
BP6 N/AThe ATM CSPEC marks BP6 as not applicable for this framework. Details ▾Hide ▴
Rule
Not applicable per ATM CSPEC v1.5.
Evidence considered
  • ATM CSPEC v1.5 lists BP6 as not applicable
Sources
case_summary.json
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
ATM BP7 is specified for synonymous and deep intronic variants, with RNA subrules for lack of splice effect.
Evidence considered
  • Variant type is missense p.(Leu1046Pro)
  • SpliceAI does not indicate a splicing mechanism
Sources
case_summary.jsonevidence.json

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.3137T>C
Protein (HGVS p.)
NP_000042.3:p.(Leu1046Pro)
GRCh38
chr11:108272591 T>C
GRCh37
chr11:108143318 T>C

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 3 / 1,613,832 alleles AF 1.86e-06 · 0 homozygotes · FAF 3.65e-06
gnomAD v2.1 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,613,832 alleles · 0 hom · FAF 3.7e-06
South Asian2 / 91,080 2.2e-05
European (non-Finnish)1 / 1,179,776 8.5e-07
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85893e-06; MAF= 0.00019%, 3/1613832 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19587e-05; MAF= 0.00220%, 2/91080 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 SupportingIn silico evidence supports a deleterious missense effect: the REVEL score is 0.854, which is above the ATM PP3 threshold of 0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01. Details ▾Hide ▴
Rule
ATM PP3_Supporting for missense variants: REVEL >0.7333.
Evidence considered
  • REVEL 0.854
  • ATM PP3 threshold >0.7333
  • SpliceAI max delta score 0.01
Sources
prefetch.jsonevidence.jsoncase_summary.json
BP4 SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splicing threshold of 0.1, but the REVEL score is 0.854, which is above the ATM BP4 missense threshold of 0.249, so BP4 is not met. Details ▾Hide ▴
Rule
ATM BP4_Supporting for missense variants: REVEL ≤0.249; for splicing: SpliceAI ≤0.1.
Evidence considered
  • REVEL 0.854
  • SpliceAI max delta score 0.01
  • ATM BP4 missense threshold ≤0.249
Sources
prefetch.jsonevidence.jsoncase_summary.json
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
ATM BP7 is specified for synonymous and deep intronic variants, with RNA subrules for lack of splice effect.
Evidence considered
  • Variant type is missense p.(Leu1046Pro)
  • SpliceAI does not indicate a splicing mechanism
Sources
case_summary.jsonevidence.json

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 3 / 1,613,832 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.85893e-06; MAF= 0.00019%, 3/1613832 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19587e-05; MAF= 0.00220%, 2/91080 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: 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.