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ATM
Final classification
VUS
ATM c.838A>G · p.Ile280Val
ATM

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 0.00019% (3/1,613,222 alleles), no homozygotes, far below the panel's 0.001% threshold.

Gene
ATM
Transcript
NM_000051.4
HGVS · transcript:coding
NM_000051.4:c.838A>G
Consequence
N/A
GRCh38
chr11:108244963 A>G
GRCh37
chr11:108115690 A>G
Basis This variant was classified under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel specifications for ATM (version 1.5), which take precedence over the generic ACMG/AMP guidelines. Two supporting-strength criteria were applied: PM2 (Supporting), because the variant is extremely rare in population databases, and BP4 (Supporting), because computational prediction strongly favors a benign effect. Because these oppose each other, Rule 31 of the panel's combination rules (at least one benign-supporting plus one pathogenic-supporting criterion) is satisfied, which maps to 'Uncertain Significance - Conflicting Evidence', i.e., VUS. No pathogenic, likely pathogenic, benign, or likely benign rule is satisfied. The only functional study of this variant uses an assay the panel has not approved; its 'Intermediate' result warrants expert review but does not change the classification. ▾
This variant was classified under the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel specifications for ATM (version 1.5), which take precedence over the generic ACMG/AMP guidelines. Two supporting-strength criteria were applied: PM2 (Supporting), because the variant is extremely rare in population databases, and BP4 (Supporting), because computational prediction strongly favors a benign effect. Because these oppose each other, Rule 31 of the panel's combination rules (at least one benign-supporting plus one pathogenic-supporting criterion) is satisfied, which maps to 'Uncertain Significance - Conflicting Evidence', i.e., VUS. No pathogenic, likely pathogenic, benign, or likely benign rule is satisfied. The only functional study of this variant uses an assay the panel has not approved; its 'Intermediate' result warrants expert review but does not change the classification.
Classification rationale
PM2 BP4 VUS
ATM c.838A>G

PM2 (Supporting): extremely rare in population databases - gnomAD v4.1 allele frequency 0.00019% (3/1,613,222 alleles), no homozygotes, far below the panel's 0.001% threshold. BP4 (Supporting): computational prediction strongly favors a benign effect - REVEL 0.043, well below the panel's 0.249 threshold. Final classification: VUS (Uncertain Significance - Conflicting Evidence), produced by Rule 31 (one pathogenic-supporting criterion plus one benign-supporting criterion).

PM2 + BP4 → VUS
Gene diagram · NM_000051.4 · variants mapped to exon structure
ATM NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 10 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
Met (supporting): the variant is extremely rare, with a gnomAD v4.1 allele frequency of 0.00019% (3/1,613,222 alleles), no homozygotes, and all subpopulation frequencies far below the panel's 0.001% threshold; gnomAD v2.1 shows a similarly low frequency.
gnomad_v4gnomad_v2gnomad_canada
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
✓
BP4 supporting Benign
Met (supporting): the REVEL score of 0.043 is well below the panel's 0.249 threshold, strongly predicting a benign effect on protein function; splicing prediction is likewise unremarkable.
REVEL score 0.043 (BP4 missense threshold <= 0.249 met)SpliceAI max delta score 0.00 (BP4 splicing threshold <= 0.1 met under VCEP literal text; superseded for missense by curator override - outcome unchanged)BayesDel score -0.43543 (corroborating benign-leaning prediction; not part of VCEP rule)
spliceai ↗cspec ↗
Assessed · not applied
Pathogenic
PS1 Not met: PS1 requires an established pathogenic variant producing the identical amino acid change (p.Ile280Val), and none exists.
PS3 Not met: no functional assay approved by the ATM expert panel has tested this variant.
PS4 Not met: no variant-specific case-control enrichment exists for c.838A>G.
PM3 Not met: no Ataxia-Telangiectasia proband carrying this variant was identified.
PP1 Not assessed: no family segregation data (genotyped affected relatives, pedigree, or phase information) were available for this variant, and no publication reports it.
PP3 Not met: both computational sub-paths defined by the ATM panel fail.
Benign
BA1 Not met: the variant is far too rare for this stand-alone benign criterion.
BS1 Not met: population frequency does not approach the strong-benign threshold - 0.00019% versus the required 0.05%.
BS3 Not met: no assay approved by the ATM expert panel shows this variant preserves ATM function.
BP2 Not met: no unaffected carrier of this variant with a pathogenic ATM variant in trans was identified.
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= 1.85963e-06; MAF= 0.00019%, 3/1613222 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.333e-05; MAF= 0.00333%, 2/60006 alleles, homozygotes = 0); grpmax FAF= 5.53e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.99186e-06; MAF= 0.00040%, 1/250510 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.8967e-05; MAF= 0.00290%, 1/34522 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019% · 3 / 1,613,222
0 hom · FAF 0.00055%
Admixed American
2 / 60,006
0.0033%
European (non-Finnish)
1 / 1,179,796
8.5e-05%
+ 8 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004% · 1 / 250,510
0 hom
Admixed American
1 / 34,522
0.0029%
+ 7 not observed (African/African 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 (6 clinical laboratories). (ClinVarID = 407462)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.043. BayesDel score = -0.43543.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.
Rule & framework references · cited for criterion definitions, not variant evidence
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.
32761968 ↗ Exon splicing analysis of intronic variants in multigene cancer panel testing for hereditary breast/ovarian cancer.
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
34262154 ↗ Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia. 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
35534704 ↗ The genetics of hereditary cancer risk syndromes in Brazil: a comprehensive analysis of 1682 patients. CLINVAR
20050888 ↗ EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. CLINVAR