Starting
Initialising…
0%
ATM
Final classification
Likely Benign
ATM c.7974T>C · p.Asn2658=
ATM

NM_000051.4:c.7974T>C is a synonymous variant p.(Asn2658=) in ATM exon 54, located well outside the canonical splice consensus regions.

Gene
ATM
Transcript
NM_000051.4
HGVS · transcript:coding
NM_000051.4:c.7974T>C
Consequence
N/A
GRCh38
chr11:108333932 T>C
GRCh37
chr11:108204659 T>C
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, 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, BP7 supporting; maps to Likely Benign.
Classification rationale
PM2 BP4BP7 Likely Benign
ATM c.7974T>C

NM_000051.4:c.7974T>C is a synonymous variant p.(Asn2658=) in ATM exon 54, located well outside the canonical splice consensus regions. SpliceAI predicts no splice impact (max delta score = 0.00).1 This variant is present in gnomAD v4.1 at very low frequency (total AF = 0.00031%, 5/1,611,834 alleles, 0 homozygotes), highest in East Asian population (sub-population AF = 0.011%).2 ClinVar reports this variant as Likely benign (4 clinical laboratories) and Benign (1 laboratory); review status: criteria provided, single submitter (ClinVar Variation ID: 414583).3 The ClinGen HBOP VCEP supplementary table (PMID:40580951, Table S1) classifies this variant as Likely benign with an eDA score of 3.10e-06.4 BP7_Supporting is met: synonymous variant outside donor +7 and acceptor -21 splice regions with no predicted splice impact (SpliceAI = 0.0).5 BP4_Supporting is met: no predicted impact via splicing (SpliceAI max delta = 0.0 ≤ 0.1). Note partial overlap with BP7.6 PM2_Supporting is met: gnomAD v4.1 total allele frequency (0.00031%) is ≤ 0.001% VCEP threshold. Per VCEP guidance, PM2 is not considered conflicting evidence for variants that otherwise are likely benign/benign.7 No pathogenic criteria beyond PM2_Supporting are met. Multiple benign supporting criteria (BP7, BP4) are met with no conflicting pathogenic evidence per VCEP PM2 guidance.8 The ClinGen HBOP Expert Panel classification from the VCEP supplementary table is Likely benign, which is concordant with the evidence-based assessment.9

PM2 + BP4 + BP7 Likely Benign
4 vcep_suppl_tables1_pmid_40580951
9 vcep_suppl_tables1_pmid_40580951
Gene diagram · NM_000051.4 · variants mapped to exon structure
ATM NM_000051.4
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 · 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= 3.10206e-06; MAF= 0.00031%, 5/1611834 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000111418; MAF= 0.01114%, 5/44876 alleles, homozygotes = 0); grpmax FAF= 4.346e-05.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 2.38796e-05; MAF= 0.00239%, 6/251260 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000326193; MAF= 0.03262%, 6/18394 alleles, homozygotes = 0); grpmax FAF= 0.00014146.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.00031% · 5 / 1,611,834
      0 hom · FAF 0.0043%
      East Asian
      5 / 44,876
      0.011%
      + 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
      gnomAD v2.1
      0.0024% · 6 / 251,260
      0 hom · FAF 0.014%
      East Asian
      6 / 18,394
      0.033%
      + 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
      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 (4 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 414583)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
      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 not previously been reported in somatic cancers (COSMIC).
      Hotspots
      This variant does not lie in a statistically significant hotspot.
      Sources & reference links
      9Sources
      CSpec VCEP
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 7 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
      24432435 ↗ PMID 24432435 CLINVAR
      26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR
      31429903 ↗ Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. CLINVAR
      35802134 ↗ ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). 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