Starting
Initialising…
0%
ATM
Final classification
Likely Benign
ATM c.8751C>T · p.Gly2917=
ATM

This synonymous variant (NM_000051.3:c.8751C>T, p.Gly2917=) is located in exon 62 of ATM, well removed from canonical splice sites (52 nt from the donor, 97 nt from the acceptor). SpliceAI predicts no splice impact (max delta = 0.01), consistent with BP4_Supporting under the ATM HBOP VCEP v1.5.0.

Gene
ATM
Transcript
NM_000051.3
HGVS · transcript:coding
NM_000051.3:c.8751C>T
Consequence
N/A
GRCh38
chr11:108353845 C>T
GRCh37
chr11:108224572 C>T
Basis Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting, BP6 supporting benign, BP7 supporting; maps to Likely Benign.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting, BP6 supporting benign, BP7 supporting; maps to Likely Benign.
Classification rationale
PM2 BP4BP6BP7 Likely Benign
ATM c.8751C>T

This synonymous variant (NM_000051.3:c.8751C>T, p.Gly2917=) is located in exon 62 of ATM, well removed from canonical splice sites (52 nt from the donor, 97 nt from the acceptor). SpliceAI predicts no splice impact (max delta = 0.01), consistent with BP4_Supporting under the ATM HBOP VCEP v1.5.0.1 As a synonymous variant not near splice consensus boundaries and with no predicted or observed splice defect, BP7_Supporting is met under ATM VCEP v1.5.0.2 The variant is extremely rare in population databases: absent from gnomAD v2.1 and present at AF = 0.00019% (3/1,613,812 alleles, grpmax FAF = 6.8e-07) in gnomAD v4.1, meeting PM2_Supporting under ATM VCEP v1.5.0 (threshold ≤ 0.001%).3 This variant has been classified as Likely Benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer VCEP (ClinVar Variation ID 453745, reviewed by expert panel). Clinical laboratory submissions include Likely Benign (2 labs), Benign (1 lab), and Uncertain Significance (1 lab).4 PVS1, PS1, and PM5 are not applicable as the variant is synonymous and does not cause a null effect, amino acid change, or premature termination codon. PS3 and BS3 functional assay data (ATM kinase/rescue assays) are not available. PS4 case-control data and PP1 segregation data are absent. BA1 and BS1 population frequency thresholds are not met. PP3 computational evidence for pathogenicity is not met.5 Under the ATM VCEP v1.5.0 combination rules (adapted from Richards et al. 2015), the met criteria include two benign supporting criteria (BP4, BP7) and one pathogenic supporting criterion (PM2). Per the VCEP classification framework, this constellation of ≥1 Benign Supporting and ≥1 Pathogenic Supporting results in Uncertain Significance - Conflicting Evidence (Rule 31). However, the ClinGen HBOP VCEP expert panel has classified this variant as Likely Benign, suggesting additional benign evidence (such as RNA splicing data from PMID 34974520) may have been considered in the expert panel curation that is not independently verifiable from the available case materials.6

PM2 + BP4 + BP6 + BP7 Likely Benign
Gene diagram · NM_000051.3 · variants mapped to exon structure
ATM NM_000051.3
Fetching transcript structure from UCSC…
Applied criteria · 4 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 benign
      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= 1.85895e-06; MAF= 0.00019%, 3/1613812 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54249e-06; MAF= 0.00025%, 3/1179944 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
      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
      0.00019% · 3 / 1,613,812
      0 hom · FAF 6.8e-05%
      European (non-Finnish)
      3 / 1,179,944
      0.00025%
      + 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
      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 benign (2 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Likely Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 453745)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
      Functional / OncoKB screenshot
      Functional Unknown Oncogenic Effect
      OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
      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 previously been reported in somatic cancers (COSMIC; COSV113466872, n = 1 times).
      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 · 10 PMIDs not cited in assessment
      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
      15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
      17508274 ↗ Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors. CLINVAR
      18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR
      20301317 ↗ Hereditary Ataxia Overview. CLINVAR
      20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR
      20301790 ↗ Ataxia-Telangiectasia. CLINVAR
      20050888 ↗ EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR