PM2_supporting is met: the variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles), well below the VCEP ATM PM2_supporting threshold of ≤0.001%.1 PP3 is met: REVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. AlphaMissense is 0.98 and SpliceAI predicts no splicing impact (max delta=0.00).2 No other pathogenic or benign criteria are met. PVS1, PS1, PS3, PS4, PM5, and PP1 are not applicable or not met. BA1, BS1, BS3, BP2, and BP4 are not met. Remaining criteria (PS2, PM1, PM6, PP2, PP4, PP5, BS2, BS4, BP1, BP5, BP6, BP7) are not applicable per VCEP ATM v1.5.0 specifications.3 With PM2_supporting and PP3 as the only criteria met (two pathogenic supporting), there is insufficient evidence to classify this variant beyond Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules. No benign criteria are met to trigger conflicting-evidence rules.4
ATM
Final classification
VUS
ATM c.8056T>C · p.Phe2686Leu
ATM
PM2_supporting is met: the variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles), well below the VCEP ATM PM2_supporting threshold of ≤0.001%.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3
VUS
ATM c.8056T>C
PM2 + PP3
→
VUS
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 9 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and present at extremely low frequency in gnomAD v4.1 (AF=6.20e-07, 1/1,613,950 alleles; highest subpopulation NFE AF=8.48e-07, 1/1,179,832 alleles). This is well below the VCEP ATM PM2_supporting threshold of ≤0.001% (n=1 in a single subpopulation).
gnomAD v2.1: absentgnomAD v4.1: 1/1613
✓
PP3
supporting
Pathogenic
REVEL score of 0.913 exceeds the VCEP ATM PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta=0.00), consistent with a purely missense effect. BayesDel score is 0.331.
REVEL: 0.913 (>0.7333 threshold)SpliceAI: max delta 0.00 (no splicing impact)BayesDel: 0.331
Assessed · not applied
Pathogenic
PS1
No known pathogenic or likely pathogenic missense variant at the same residue (p.Phe2686) with a different amino acid change was identified in ClinVar or VCEP reference datasets.
PS3
No variant-specific experimental functional assay data (kinase activity or radiosensitivity rescue) are available for p.Phe2686Leu.
PS4
No case-control study demonstrating statistically significant enrichment of this variant in affected individuals.
PP1
No segregation data available for this variant.
Benign
BA1
gnomAD v4.1 overall allele frequency is 6.20e-07 (0.000062%), well below the VCEP ATM BA1 threshold of >0.5% (Grpmax Filtering AF).
BS1
gnomAD v4.1 overall allele frequency is 6.20e-07 (0.000062%), well below the VCEP ATM BS1 threshold of >0.05% (Grpmax Filtering AF).
BS3
No experimental functional data demonstrating rescue of ATM kinase activity or radiosensitivity for p.Phe2686Leu.
BP2
No observation of this variant in trans with a pathogenic variant in an unaffected (non-A-T) individual.
BP4
REVEL score of 0.913 far exceeds the VCEP ATM BP4 threshold of ≤0.249 for missense variants.
N/A · 17
PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19598e-07; MAF= 0.00006%, 1/1613950 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47578e-07; MAF= 0.00008%, 1/1179832 alleles, homozygotes = 0).
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
6.2e-05%
· 1 / 1,613,950
0 hom
0 hom
European (non-Finnish) 1 / 1,179,832 |
8.5e-05% |
+ 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 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 490724)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.331457.
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.
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; COSV53747617, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 8 PMIDs not cited in assessment
17968022 ↗
Mutation status of the residual ATM allele is an important determinant of the cellular response to chemotherapy and survival in patients with chronic lymphocytic leukemia containing an 11q deletion.
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
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
31429931 ↗
Whole exome and targeted gene sequencing to detect pathogenic recessive variants in early onset cerebellar ataxia.
CLINVAR