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
Final classification
Likely Pathogenic
PM3PM2PS3
ATM
c.6200C>A
p.Ala2067Asp
This variant
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 ↗
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.
Gene diagram
· NM_000051.4 · variants mapped to exon structure
ATM
NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 9 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
PS3
supporting
Pathogenic
In a published functional study, lymphoblastoid cells from affected individuals expressed only small amounts of ATM protein, showed no ATM Ser1981 autophosphorylation, and had trace-to-absent phosphorylation of downstream ATM targets; engineered cells expressing the variant also showed trace-to-absent downstream signaling. This demonstrates failure of an ATM-specific functional feature and supports PS3 at supporting strength.
PMID:25077176 functional assays showed markedly impaired ATM protein expression and ATM-specific signaling.
PM2
supporting
Pathogenic
This variant is very rare in gnomAD v4.1, with a total allele frequency of 3.10452e-06 (0.00031%), 5 of 1610556 alleles observed, no homozygotes, and grpmax filtering allele frequency 8e-07. This is below the ATM PM2 threshold of 0.001%, supporting PM2 at supporting strength.
gnomAD v4.1 total AF 3.10452e-065/1610556 alleles0 homozygotes.
PM3
strong
Pathogenic
This variant has been reported in multiple affected individuals with variant ataxia-telangiectasia, including homozygous affected members in Canadian Mennonite families. Under the ATM PM3 framework, homozygous affected individuals can contribute points up to the cap of two individuals; this supports PM3 at strong strength.
PM3 table allows homozygous affected individualsmaximum two individuals.PMID:22345219 reported 13 members from 3 families with the homozygous ATM founder mutation and variant A-T.
Assessed · not applied
· 6 not met · 3 not assessed
Pathogenic
PS1
No previously established pathogenic ATM variant producing the same amino acid substitution was identified from the available evidence, so PS1 is not met.
PS4
Published case reports and series were identified, but no qualifying variant-specific case-control result with p-value 0.05 or less and odds ratio, hazard ratio, or relative risk of at least 2, or lower 95% confidence interval of at least 1.5, was confirmed from the available evidence.
PP1
Affected family members with this variant were reported, but the available evidence does not provide sufficiently clear segregation counting under the ATM autosomal recessive PP1 framework to assign a PP1 strength level independently of PM3.
PP3
For this missense variant, the REVEL score is 0.435, which is below the ATM PP3 threshold of greater than 0.7333.
Benign
BA1
The gnomAD v4.1 grpmax filtering allele frequency is 8e-07, which is far below the ATM BA1 threshold of greater than 0.5%.
BS1
The gnomAD v4.1 grpmax filtering allele frequency is 8e-07, which is well below the ATM BS1 threshold of greater than 0.05%.
BS3
Available functional evidence does not show rescue of ATM function.
BP2
No unaffected adult individual with this variant observed in trans with a pathogenic or likely pathogenic ATM variant, and no qualifying benign co-occurrence evidence was identified.
BP4
The REVEL score is 0.435, which is above the ATM BP4 missense threshold of 0.249 or less, so missense computational evidence does not support BP4.
N/A · 16
PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
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. 8 further PMIDs triaged but not cited — see Sources & references.
Variant ataxia-telangiectasia presenting as primary-appearing dystonia in Canadian Mennonites.
Found
reported 13 members from 3 families with the homozygous ATM founder mutation and variant A-T.
Applied to
→PM3
strong
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.
Found
functional assays showed markedly impaired ATM protein expression and ATM-specific signaling.
Applied to
→PS3
supporting
→PM3
strong
Sources & reference links
Triaged references · 8 PMIDs not cited in assessment
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