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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.

Gene
ATM
Transcript
NM_000051.3
HGVS · transcript:coding
NM_000051.3:c.8546G>C
Consequence
N/A
GRCh38
chr11:108345870 G>C
GRCh37
chr11:108216597 G>C
Basis 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.
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

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

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 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
      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= 1.23938e-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
      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
      Not observed in any ancestry group.
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      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)
      SpliceAI screenshot
      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 / 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.
      Sources & reference links
      8Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      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
      15279808 ↗ Functional consequences of sequence alterations in the ATM gene. CLINVAR
      23667852 ↗ Identification of ATM mutations in Korean siblings with 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
      28508083 ↗ Structures of closed and open conformations of dimeric human ATM. CLINVAR
      31097817 ↗ Structural basis of allosteric regulation of Tel1/ATM kinase. 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
      9887333 ↗ Characterization of ATM gene mutations in 66 ataxia telangiectasia families. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR