This missense variant (c.8546G>C, p.Arg2849Pro) in ATM is extremely rare in population databases, observed at an allele frequency of 0.00012% in gnomAD v4.1 (2/1,613,706 alleles), supporting PM2_Supporting under the ClinGen HBOP ATM VCEP v1.5.0 specifications.1 The REVEL in silico predictor yields a score of 0.919, exceeding the VCEP PP3 threshold of >0.733, and SpliceAI predicts no splicing impact (max delta 0.01), supporting PP3 at supporting strength.2 Exploratory functional evidence from high-throughput assays (PMID 31097817, PMID 29650054) suggests the variant impairs ATM kinase activity, which may support PS3. However, full-text verification of variant mention and confirmation that the assays meet VCEP-approved functional thresholds remain pending. The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel has classified this variant as Likely Pathogenic (ClinVar variation ID 490737, review status: reviewed by expert panel). Seven clinical laboratories concur (6 Likely pathogenic, 1 Pathogenic).3 Under the VCEP combination rules, the currently confirmed criteria (PM2_Supporting, PP3) yield 2 pathogenic supporting points, which is insufficient to reach Likely Pathogenic. The expert panel's LP classification likely incorporates additional evidence (PS3 functional data, PM3 trans observations, or PS1 comparator data) not fully verified in this automated adjudication.4
ATM
Final classification
VUS
ATM c.8546G>C · p.Arg2849Pro
ATM
This missense variant (c.8546G>C, p.Arg2849Pro) in ATM is extremely rare in population databases, observed at an allele frequency of 0.00012% in gnomAD v4.1 (2/1,613,706 alleles), supporting PM2_Supporting under the ClinGen HBOP ATM VCEP v1.5.0 specifications.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PM2 supporting, PP3 supporting, PP5 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3PP5
VUS
ATM c.8546G>C
PM2 + PP3 + PP5
→
VUS
Gene diagram
· NM_000051.3 · variants mapped to exon structure
ATM
NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 9 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is extremely rare in population databases. In gnomAD v4.1, it is observed at an overall allele frequency of 0.00012% (2/1,613,706 alleles, 0 homozygotes), which is well below the VCEP PM2_Supporting threshold of ≤0.001%. It is absent from gnomAD v2.1. The highest subpopulation frequency is in Remaining individuals at 0.00160% (1/62,468). PM2_Supporting applies.
gnomAD v4.1: AF=0.00012% (2/1613706)
✓
PP3
supporting
Pathogenic
REVEL score is 0.919, exceeding the VCEP PP3 threshold of >0.733 for missense variants. SpliceAI confirms no confounding splice impact (max delta score 0.01). PP3 applies at supporting strength.
REVEL score 0.919 (>0.733 VCEP threshold)SpliceAI max delta 0.01 (no splicing confounder).
✓
PP5
supporting
Pathogenic
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.
VCEP specification explicitly marks PP5 as not applicable per ClinGen SVI VCEP Review Committee.ClinVar expert panel classification
Assessed · not applied
Pathogenic
PS1
PS1 (same amino acid change as a previously established pathogenic variant regardless of nucleotide change) requires a known P/LP missense variant at Arg2849 with a different nucleotide change.
PS3
Exploratory evidence recovery identified functional data from PMID 31097817 (flow cytometry-based ATM kinase assay) and PMID 29650054 (saturation genome editing) reporting damaging effects for p.R2849P.
PS4
No case-control study with variant-level odds ratio or relative risk has been identified in the clinical literature.
PP1
No segregation data has been identified for this variant.
Benign
BA1
The overall allele frequency in gnomAD v4.1 is 0.00012%, far below the VCEP BA1 stand-alone threshold of Grpmax Filtering AF >0.5%.
BS1
The overall allele frequency in gnomAD v4.1 is 0.00012%, below the VCEP BS1 strong benign threshold of Grpmax Filtering AF >0.05%.
BS3
Available functional evidence (exploratory findings from PMID 31097817 and PMID 29650054) indicates a damaging effect on ATM function rather than rescue of ATM-specific features.
BP2
No evidence has been identified of this variant observed in trans with a known pathogenic ATM variant in an unaffected individual aged 18 years or older.
BP4
REVEL score is 0.919, which exceeds the VCEP BP4 threshold of ≤0.249 for missense variants.
N/A · 16
PVS1 · PS2 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP4 · 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= 1.23938e-06; MAF= 0.00012%, 2/1613706 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.60082e-05; MAF= 0.00160%, 1/62468 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,613,706
0 hom
0 hom
Remaining individuals 1 / 62,468 |
0.0016% |
European (non-Finnish) 1 / 1,179,842 |
8.5e-05% |
+ 8 not observed (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 Likely pathogenic (6 clinical laboratories) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 490737)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.919. BayesDel score = 0.448409.
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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
11805335 ↗
Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer.
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
34242744 ↗
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR