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ATMc.7527G>ANot classified
Print report
Variant interpretation report

ATM c.7527G>A, p.(Met2509Ile)

NM_000051.3:c.7527G>A NP_000042.3:p.(Met2509Ile) View identifiers
Classification
Not classified

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. Select a step to read what it means.

Not classified yet.Select a step to read what it means.

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. 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000051.3:c.7527G>A is absent from gnomAD v4.1 (allele frequency = 0). This meets the ATM VCEP v1.5 threshold for PM2_Supporting (frequency ≤0.001% in gnomAD v4).

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

REVEL score of 0.184 is ≤0.249, meeting the ATM VCEP v1.5 BP4 threshold for missense variants. SpliceAI max delta score of 0.06 is ≤0.1, indicating no predicted splicing impact. BayesDel score of -0.366 is consistent with a benign in silico prediction.

Recorded classification: Not classified

ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 v1.5 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.

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
0.060 maximum delta

Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions

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

Context only ClinVar ↗
Functional evidence
Statement recorded

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

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.

26 criteria with recorded statuses: 2 met · 10 not met · 0 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000051.3:c.7527G>A (Met2509Ile) is a missense variant in ATM exon 51. It is absent from gnomAD v4.1 population databases (PM2_Supporting).

Multiple in silico computational tools predict a benign effect: REVEL score 0.184 (BP4 threshold ≤0.249); SpliceAI max delta 0.06 (no predicted splicing impact); BayesDel score -0.366 (BP4_Supporting).

The variant is classified as 'Non-functional' by computational meta-prediction in Suppl_TableS1 (PMID 40580951, combined score -1.87, medium-high confidence), but this is a computational prediction rather than experimental functional data and does not meet VCEP requirements for PS3 or BS3.

This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories and as Likely benign by one clinical laboratory (ClinVar Variation ID: 407522). Under VCEP v1.5, PP5 and BP6 are not applicable.

No variant-specific literature was identified; seven ClinVar-associated PMIDs were reviewed and none mentioned NM_000051.3:c.7527G>A.

Applying ATM VCEP v1.5 rules: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point) result in a classification of Uncertain Significance per Rule 31 (conflicting evidence: ≥1 benign supporting + ≥1 pathogenic supporting).

Met · 2

PM2 SupportingNM_000051.3:c.7527G>A is absent from gnomAD v4.1 (allele frequency = 0). This meets the ATM VCEP v1.5 threshold for PM2_Supporting (frequency ≤0.001% in gnomAD v4). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (0 alleles
  • frequency = 0)
  • Absent from gnomAD v2.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v4 ↗cspec ↗
BP4 SupportingREVEL score of 0.184 is ≤0.249, meeting the ATM VCEP v1.5 BP4 threshold for missense variants. SpliceAI max delta score of 0.06 is ≤0.1, indicating no predicted splicing impact. BayesDel score of -0.366 is consistent with a benign in silico prediction. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.184 (threshold ≤0.249)
  • SpliceAI max delta: 0.06 (threshold ≤0.1)
  • BayesDel: -0.366 (benign prediction)
Sources
revelspliceai ↗bayesdelcspec ↗

Not met · 10 · evaluated, threshold not reached

PVS1 NM_000051.3:c.7527G>A is a missense variant (Met2509Ile) and does not meet PVS1 null-variant criteria under the ATM VCEP v1.5. PVS1 is applicable only to nonsense, frameshift, canonical ±1/2 splice sites, initiation codon, or exon deletion variants. Details ▾Hide ▴
Evidence considered
  • Missense variant (Met2509Ile) is not a null variant
  • Variant falls outside PVS1 null-variant buckets
Sources
vcep_atm_pvs1_1_5pvs1_variant_assessment
PS1 No previously established pathogenic variant resulting in the same amino acid change (Met2509Ile) via a different nucleotide substitution has been identified. Alternate nucleotide changes at c.7527 (c.7527G>T and c.7527G>C) are also not classified as pathogenic in ClinVar. Details ▾Hide ▴
Evidence considered
  • c.7527G>T (Met2509Ile): no ClinVar classification
  • c.7527G>C (Met2509Ile): ClinVar Uncertain significance
  • No pathogenic variant with same amino acid change exists
Sources
vcep_atm_ps1_1_5vcep_suppl_tables1_pmid_40580951clinvar ↗
PS3 No variant-specific experimental functional data is available for NM_000051.3:c.7527G>A. The variant is computationally classified as 'Non-functional' in Suppl_TableS1 (PMID 40580951, combined score -1.87, medium-high confidence), but this is a computational prediction, not experimental rescue assay data. ATM VCEP v1.5 requires experimental functional evidence (failure to rescue ATM-specific phosphorylation targets ± radiosensitivity in ATM-null cells) for PS3 application. Details ▾Hide ▴
Evidence considered
  • Suppl_TableS1 classifies variant as Non-functional (computational prediction)
  • No experimental rescue assay data identified for this variant
  • Variant not listed in approved VCEP functional assay validation controls
Still missing
  • Absence of experimental functional studies (ATM kinase activity rescue or radiosensitivity rescue assays)
Sources
vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PS4 No case-control studies with statistical significance have been reported for this variant. ATM VCEP v1.5 requires case-control studies demonstrating p-value ≤0.05 and OR/RR ≥2 or lower 95% CI ≥1.5. Details ▾Hide ▴
Evidence considered
  • No case-control data identified in the literature for this variant
Still missing
  • Lack of case-control or cohort studies evaluating variant prevalence in affected populations
Sources
cspec ↗
PP1 No segregation data is available for this variant. ATM VCEP v1.5 applies PP1 for autosomal recessive conditions only, requiring co-segregation in affected relatives with both variants identified. For AD conditions, PP1 is not used due to low penetrance. Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • Absence of segregation analysis in affected families
Sources
cspec ↗
PP3 REVEL score of 0.184 does not exceed the ATM VCEP v1.5 threshold of >0.7333 for missense variants. SpliceAI max delta score of 0.06 does not exceed the threshold of ≥0.2 for splicing variants. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.184 (threshold >0.7333)
  • SpliceAI max delta: 0.06 (threshold ≥0.2)
  • BayesDel: -0.366 (benign prediction)
Sources
revelspliceai ↗cspec ↗
BA1 NM_000051.3:c.7527G>A is absent from gnomAD v4.1. The ATM VCEP v1.5 BA1 threshold of Grpmax Filtering AF >0.5% is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (allele frequency = 0)
Sources
gnomad_v4 ↗cspec ↗
BS1 NM_000051.3:c.7527G>A is absent from gnomAD v4.1. The ATM VCEP v1.5 BS1 threshold of Grpmax Filtering AF >0.05% is not met. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (allele frequency = 0)
Sources
gnomad_v4 ↗cspec ↗
BS3 No experimental functional data demonstrating that this variant rescues ATM function (kinase activity or radiosensitivity) in ATM-null cells is available. The computational classification as 'Non-functional' from Suppl_TableS1 is a prediction, not experimental rescue assay data. ATM VCEP v1.5 requires experimental evidence of functional rescue for BS3 application. Details ▾Hide ▴
Evidence considered
  • No experimental rescue assay data identified
  • Variant not tested in approved VCEP functional assays
Still missing
  • Absence of experimental functional studies demonstrating normal ATM function
Sources
vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP2 No co-occurrence data (homozygous or in trans with a pathogenic ATM variant in unaffected individuals) is available for this variant. ATM VCEP v1.5 BP2 scoring requires proband-level data per the PM3/BP2 table. Details ▾Hide ▴
Evidence considered
  • No co-occurrence data available
Still missing
  • Absence of unaffected individuals with this variant in trans or homozygous with a pathogenic ATM variant
Sources
vcep_atm_pm3_bp2_1_5
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPATM VCEP v1.5 specifies: do not use for AD or AR disease as informative de novo occurrences have not yet been observed. Details ▾Hide ▴
Sources
cspec ↗
PM1 VCEPATM VCEP v1.5 specifies: do not use. Benign and pathogenic variants are known to occur within the same domains, and germline mutational hotspots are not well defined at this time. Details ▾Hide ▴
Sources
cspec ↗
PM5 N/AATM VCEP v1.5 specifies PM5_Supporting applies to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or splice variants with PTC upstream of p.Arg3047. This variant is a missense substitution (Met2509Ile); PM5 does not apply. Details ▾Hide ▴
Sources
cspec ↗pm5_candidates
PM6 VCEPATM VCEP v1.5 specifies: 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. Details ▾Hide ▴
Sources
cspec ↗
PP2 VCEPATM VCEP v1.5 specifies: do not use. ATM does not have a defined low rate of missense benign variation. Details ▾Hide ▴
Sources
cspec ↗
PP4 VCEPATM VCEP v1.5 specifies: do not use. For AD: breast cancer has multiple genetic etiologies with no distinguishing features. For AR: such evidence is built into the PM3/BP2 table. Details ▾Hide ▴
Sources
cspec ↗
PP5 VCEPATM VCEP v1.5 specifies: Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
cspec ↗
BS2 VCEPATM VCEP v1.5 specifies: do not use. ATM has incomplete penetrance. Details ▾Hide ▴
Sources
cspec ↗
BS4 VCEPATM VCEP v1.5 specifies: do not use. For AD: co-segregation analysis in low-penetrance genes can yield false positives. For AR: informative instances of lack of co-segregation in A-T families are too rare. Details ▾Hide ▴
Sources
cspec ↗
BP1 VCEPATM VCEP v1.5 specifies: do not use. Missense pathogenic variants are known for ATM. Details ▾Hide ▴
Sources
cspec ↗
BP5 VCEPATM VCEP v1.5 specifies: do not use. Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance. Details ▾Hide ▴
Sources
cspec ↗
BP6 VCEPATM VCEP v1.5 specifies: Not Applicable for this VCEP. This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
Sources
cspec ↗
BP7 N/ABP7 is applicable to synonymous and deep intronic variants only under ATM VCEP v1.5. NM_000051.3:c.7527G>A is a missense variant (Met2509Ile). Details ▾Hide ▴
Evidence considered
  • Missense variant (Met2509Ile)
  • not synonymous or deep intronic
Sources
cspec ↗
PS5 N/APS5 is not defined in the ATM VCEP v1.5 specifications (ClinGen HBOP). The criterion is not part of the current VCEP framework for ATM. Details ▾Hide ▴
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.3
Coding (HGVS c.)
NM_000051.3:c.7527G>A
Protein (HGVS p.)
NP_000042.3:p.(Met2509Ile)
GRCh38
chr11:108331455 G>A
GRCh37
chr11:108202182 G>A
ClinVar
407522

Gene diagram

Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.3. Select a row to find it on the plot.

ATMNM_000051.3
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 -9 bp
0.060
SpliceAI acceptor gainat +51 bp
0.010
SpliceAI donor lossat +102 bp
0.000
SpliceAI donor gainat +333 bp
0.000
Pangolin splice lossmagnitude shown
-0.020
Pangolin splice gain
0.020

Other predictors

REVEL
0.184
BayesDel
-0.366

How the predictions were used

BP4 SupportingREVEL score of 0.184 is ≤0.249, meeting the ATM VCEP v1.5 BP4 threshold for missense variants. SpliceAI max delta score of 0.06 is ≤0.1, indicating no predicted splicing impact. BayesDel score of -0.366 is consistent with a benign in silico prediction. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.184 (threshold ≤0.249)
  • SpliceAI max delta: 0.06 (threshold ≤0.1)
  • BayesDel: -0.366 (benign prediction)
Sources
revelspliceai ↗bayesdelcspec ↗
PP3 REVEL score of 0.184 does not exceed the ATM VCEP v1.5 threshold of >0.7333 for missense variants. SpliceAI max delta score of 0.06 does not exceed the threshold of ≥0.2 for splicing variants. Details ▾Hide ▴
Evidence considered
  • REVEL score: 0.184 (threshold >0.7333)
  • SpliceAI max delta: 0.06 (threshold ≥0.2)
  • BayesDel: -0.366 (benign prediction)
Sources
revelspliceai ↗cspec ↗
BP7 N/ABP7 is applicable to synonymous and deep intronic variants only under ATM VCEP v1.5. NM_000051.3:c.7527G>A is a missense variant (Met2509Ile). Details ▾Hide ▴
Evidence considered
  • Missense variant (Met2509Ile)
  • not synonymous or deep intronic
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.184. BayesDel score = -0.365521.

6 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.
    Richards S et al. · 2015
    Standards and guidelines for the interpretation of sequence variants (Richards et al., 2015). General ACMG/AMP classification framework; does not address NM_000051.3:c.7527G>A specifically.
    Does not name this variant
    PMID 25741868 ↗
  • Hereditary Ataxia Overview.
    Adam MP et al. · 1993
    GeneReviews: Hereditary Ataxia Overview. General review of hereditary ataxias including ATM-related ataxia telangiectasia. No variant-specific discussion.
    Does not name this variant
    PMID 20301317 ↗
  • Ataxia-Telangiectasia.
    Adam MP et al. · 1993
    GeneReviews: Ataxia-Telangiectasia. Clinical overview of A-T including ATM gene. No variant-specific discussion of NM_000051.3:c.7527G>A.
    Does not name this variant
    PMID 20301790 ↗
  • EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
    van de Warrenburg BP et al. · 2014
    EFNS/ENS consensus on diagnosis and management of chronic ataxias in adulthood (van de Warrenburg et al., 2014). Provides guidance for ataxia diagnosis including ataxia telangiectasia at the gene level. Does not address NM_000051.3:c.7527G>A.
    Does not name this variant
    PMID 24418350 ↗
  • A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
    Hampel H et al. · 2015
    ACMG/NSGC practice guideline for cancer predisposition referral indications (Hampel et al., 2015). Discusses criteria for cancer genetic consultation referral. Does not address NM_000051.3:c.7527G>A.
    Does not name this variant
    PMID 25394175 ↗
  • EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
    Gasser T et al. · 2010
    EFNS guidelines on molecular diagnosis of ataxias and spastic paraplegias. Background review of ataxia diagnostic approaches including ATM. No variant-specific discussion.
    Does not name this variant
    PMID 20050888 ↗

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 0.060 Open source ↗
ClinVar 2 Uncertain significance · 1 Likely benign Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

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

gnomAD v4.1

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 Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 407522)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.184. BayesDel score = -0.365521.

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.