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ATM
Final classification
Uncertain Significance - Conflicting Evidence
ATM c.7527G>A · p.Met2509Ile
ATM

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).

Gene
ATM
Transcript
NM_000051.3
HGVS · transcript:coding
NM_000051.3:c.7527G>A
Consequence
N/A
GRCh38
chr11:108331455 G>A
GRCh37
chr11:108202182 G>A
Basis 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.
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.
Classification rationale
PM2 BP4 Uncertain Significance - Conflicting Evidence
ATM c.7527G>A

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).1 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).2 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 BS3.3 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.4 No variant-specific literature was identified; seven ClinVar-associated PMIDs were reviewed and none mentioned NM_000051.3:c.7527G>A.5 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).6

PM2 + BP4 Uncertain Significance - Conflicting Evidence
Gene diagram · NM_000051.3 · variants mapped to exon structure
ATM NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
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).
Absent from gnomAD v4.1 (0 allelesfrequency = 0)Absent from gnomAD v2.1
BP4 supporting Benign
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.
REVEL score: 0.184 (threshold ≤0.249)SpliceAI max delta: 0.06 (threshold ≤0.1)BayesDel: -0.366 (benign prediction)
Assessed · not applied
Pathogenic
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.
PS1 No previously established pathogenic variant resulting in the same amino acid change (Met2509Ile) via a different nucleotide substitution has been identified.
PS3 No variant-specific experimental functional data is available for NM_000051.3:c.7527G>A.
PS4 No case-control studies with statistical significance have been reported for this variant.
PP1 No segregation data is available for this variant.
PP3 REVEL score of 0.184 does not exceed the ATM VCEP v1.5 threshold of >0.7333 for missense variants.
Benign
BA1 NM_000051.3:c.7527G>A is absent from gnomAD v4.1.
BS1 NM_000051.3:c.7527G>A is absent from gnomAD v4.1.
BS3 No experimental functional data demonstrating that this variant rescues ATM function (kinase activity or radiosensitivity) in ATM-null cells is available.
BP2 No co-occurrence data (homozygous or in trans with a pathogenic ATM variant in unaffected individuals) is available for this variant.
N/A · 13 PS2 · PM1 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 407522)
SpliceAI screenshot
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 screenshot
Functional Unknown Oncogenic Effect
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 6 PMIDs not cited in assessment
25741868 ↗ 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. CLINVAR
20301317 ↗ Hereditary Ataxia Overview. CLINVAR
20301790 ↗ Ataxia-Telangiectasia. CLINVAR
24418350 ↗ EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. CLINVAR
25394175 ↗ 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. CLINVAR
20050888 ↗ EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. CLINVAR