The ATM c.6200C>A (p.Ala2067Asp; p.A2067D) variant has been reported in ClinVar with multiple pathogenic and likely pathogenic germline submissions, and variant-specific cancer curation has linked it to literature consistent with loss of ATM function.1 This variant is very rare in population databases, with gnomAD v4.1 showing an allele frequency of 3.10452e-06 (5/1610556 alleles), no homozygotes, and grpmax filtering allele frequency 8e-07, which supports rarity for ATM.2 In a published functional study, patient-derived and engineered cells showed markedly reduced ATM protein, absent ATM Ser1981 autophosphorylation, and trace-to-absent phosphorylation of downstream ATM targets, supporting a damaging effect on ATM function.3 Computational evidence does not meet the ATM PP3 or BP4 missense thresholds: REVEL is 0.435, BayesDel is 0.0616905, and SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01.4
ATM
Final classification
Likely Pathogenic
ATM c.6200C>A · p.Ala2067Asp
ATM
The ATM c.6200C>A (p.Ala2067Asp; p.A2067D) variant has been reported in ClinVar with multiple pathogenic and likely pathogenic germline submissions, and variant-specific cancer curation has linked it to literature consistent with loss of ATM function.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule12 (1 Pathogenic.Strong + Pathogenic.Supporting >=2) with applied criteria: PM3 strong, PM2 supporting, PS3 supporting; maps to Likely Pathogenic.
Classification rationale
PM3PM2PS3
Likely Pathogenic
ATM c.6200C>A
PM3 + PM2 + PS3
→
Likely Pathogenic
4
revelbayesdelspliceai ↗cspec ↗
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.10452e-06; MAF= 0.00031%, 5/1610556 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6057e-05; MAF= 0.00161%, 1/62278 alleles, homozygotes = 0); grpmax FAF= 8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.97905e-06; MAF= 0.00040%, 1/251316 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79647e-06; MAF= 0.00088%, 1/113682 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00031%
· 5 / 1,610,556
0 hom · FAF 8e-05%
0 hom · FAF 8e-05%
Remaining individuals 1 / 62,278 |
0.0016% |
European (non-Finnish) 4 / 1,178,006 |
0.00034% |
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 251,316
0 hom
0 hom
European (non-Finnish) 1 / 113,682 |
0.00088% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Pathogenic (11 clinical laboratories) and as Likely pathogenic (5 clinical laboratories) and as pathogenic (1 clinical laboratory). (ClinVarID = 39749)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.435. BayesDel score = 0.0616905.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
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; COSV53741904, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
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. 9 further PMIDs triaged but not cited — see Sources & References.
PMID PMID:22345219
Found
Structured finding pending for this record — see source link.
Applied to
→PM3 supports · met
PMID PMID:25077176
Found
Structured finding pending for this record — see source link.
Applied to
→PM3 supports · met
→PS3 supports · met
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25077176 ↗
A-TWinnipeg: Pathogenesis of rare ATM missense mutation c.6200C>A with decreased protein expression and downstream signaling, early-onset dystonia, cancer, and life-threatening radiotoxicity.
ONCOKB
20305132 ↗
Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.
CLINVAR
22529920 ↗
Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.
CLINVAR
23143971 ↗
Very mild presentation in adult with classical cellular phenotype of ataxia telangiectasia.
CLINVAR
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
26898890 ↗
Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR