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ATM
Final classification
VUS
ATM c.3332T>C · p.Leu1111Pro
ATM ·missense

PM2 (Supporting): gnomAD v4.1 total allele frequency 0.00031% (5/1,613,720 alleles, 0 homozygotes) is below the VCEP 0.001% threshold, and the variant is absent from gnomAD v2.1.

Gene
ATM
Transcript
NM_000051.4
HGVS · transcript:coding
NM_000051.4:c.3332T>C
Consequence
missense
exon 23
GRCh38
chr11:108279538 T>C
GRCh37
chr11:108150265 T>C
Basis Only PM2 (Supporting) is met — gnomAD v4.1 allele frequency 0.00031%, below the 0.001% threshold; with no other evidence, no VCEP combination rule matches, so the classification is Variant of Uncertain Significance. ▾
Only PM2 (Supporting) is met — gnomAD v4.1 allele frequency 0.00031%, below the 0.001% threshold; with no other evidence, no VCEP combination rule matches, so the classification is Variant of Uncertain Significance.
Classification rationale
PM2 VUS
ATM c.3332T>C missense · exon 23

PM2 (Supporting): gnomAD v4.1 total allele frequency 0.00031% (5/1,613,720 alleles, 0 homozygotes) is below the VCEP 0.001% threshold, and the variant is absent from gnomAD v2.1. Overall: Variant of Uncertain Significance — no VCEP combination rule matches a single supporting criterion with no other evidence.

PM2 → VUS
Gene diagram · NM_000051.4 · variants mapped to exon structure
ATM NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 11 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (Supporting): gnomAD v4.1 total allele frequency 0.00031% (5/1,613,720 alleles, 0 homozygotes) is below the VCEP 0.001% threshold.
gnomAD v4.1 (source gnomad_v4): total AF 3.09843e-06 (0.00031%), 5/1,613,720 alleles, 0 homozygotes; exome 4/1,461,482, genome 1/152,238; highest subpopulation NFE AF 4.23788e-06 (0.00042%, 5/1,179,836).ATM VCEP v1.5 (source cspec) PM2 rule: 'Frequency <=.001% in gnomAD v4 dataset. If n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply.'Total AF 0.00031% and NFE AF 0.00042% both fall below the 0.001% PM2 threshold; PM2_Supporting met.
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗cspec ↗
Assessed · not applied
Pathogenic
PS1 Not met: no established pathogenic variant producing p.Leu1111Pro exists — ClinVar lists this exact variant as uncertain significance (7 laboratories).
PS3 Not met: a directly measured functional screen shows the variant retains ATM function (classified Functional), the opposite of the loss-of-function evidence PS3 requires.
PS4 Insufficient evidence was available: no case-control or enrichment study of this variant has been published.
PM3 Insufficient evidence was available: no ataxia telangiectasia proband genotyping data exists to assign PM3 points.
PP1 Insufficient evidence was available: no family segregation data was reported for this variant.
PP3 Not met: REVEL 0.644 is below the >0.7333 threshold, and SpliceAI max delta 0.01 is below the >=0.2 threshold.
Benign
BA1 Not met: gnomAD grpmax allele frequency 0.000124% is about 4,000-fold below the >0.5% threshold.
BS1 Not met: gnomAD grpmax allele frequency 0.000124% is about 400-fold below the >0.05% threshold.
BS3 Insufficient evidence was available: the only functional result (variant retains ATM function) comes from an assay the ATM VCEP has not approved.
BP2 Insufficient evidence was available: no unaffected carrier of this variant with a pathogenic ATM variant in trans was reported.
BP4 Not met: REVEL 0.644 exceeds the <=0.249 threshold; a recorded lab-curator override excludes the SpliceAI sub-path for missense variants.
N/A · 16 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.09843e-06; MAF= 0.00031%, 5/1613720 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 4.23788e-06; MAF= 0.00042%, 5/1179836 alleles, homozygotes = 0); grpmax FAF= 1.24e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/250754 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16228 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031% · 5 / 1,613,720
0 hom · FAF 0.00012%
European (non-Finnish)
5 / 1,179,836
0.00042%
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent · 0 / 250,754
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories). (ClinVarID = 230062)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.644. BayesDel score = 0.101685.
SpliceAI ↗
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 previously been reported in somatic cancers (COSMIC; COSV99592016, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 7 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
40580951 ↗ Functional assessment of all ATM SNVs using prime editing and deep learning. CLINVAR
20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR
20301790 ↗ Ataxia-Telangiectasia. CLINVAR
24366402 ↗ 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. CLINVAR
24418350 ↗ EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. CLINVAR
35802134 ↗ ACMG SF v3.1 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). CLINVAR