Starting
Initialising…
0%
ATM
Final classification
VUS
ATM c.1009C>T · p.Arg337Cys
ATM

NM_000051.4:c.1009C>T (p.Arg337Cys) is a missense variant in ATM exon 8.

Gene
ATM
Transcript
NM_000051.4
HGVS · transcript:coding
NM_000051.4:c.1009C>T
Consequence
N/A
GRCh38
chr11:108247071 C>T
GRCh37
chr11:108117798 C>T
Basis Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: BS3 supporting benign; no rule matched the adjudicated criteria.
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: BS3 supporting benign; no rule matched the adjudicated criteria.
Classification rationale
BS3 VUS
ATM c.1009C>T

NM_000051.4:c.1009C>T (p.Arg337Cys) is a missense variant in ATM exon 8. This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00892% (144/1,613,688 alleles, 0 homozygotes) with a grpmax filtering allele frequency of 0.021% in the Admixed American population.1 This variant does not meet PM2_Supporting (frequency ≤0.001% required), BS1 (>0.05% required), or BA1 (>0.5% required) under ATM VCEP population thresholds.2 This variant has been reported in ClinVar (Variation ID 127327) as Uncertain Significance by 18 clinical laboratories and as Likely Benign by 3 clinical laboratories; no submitter classifies it as pathogenic.3 The variant has been reported 80 times in somatic cancers (COSMIC COSV53723836) and OncoKB classifies it as Likely Oncogenic with a loss-of-function effect in the somatic context.4 Computational predictors do not support a deleterious effect: REVEL score is 0.36 (VCEP PP3 threshold >0.7333, BP4 threshold ≤0.249), SpliceAI max delta is 0.10, and BayesDel is 0.067.5 The ATM VCEP functional dataset (Suppl_TableS1, PMID 40580951) classifies this variant as 'Functional' (combined score -0.65, high confidence) based on integrated functional and evolutionary scores, meeting BS3_Supporting under VCEP rules.6 PVS1, PS1, PS2, PM1, PM5, PM6, PP2, PP4, PP5, BS2, BS4, BP1, BP5, BP6, and BP7 are not applicable under ATM VCEP v1.5.0 for this variant type.7 No case-control study demonstrates enrichment of this variant in affected individuals (PS4 not met), and no segregation data are available (PP1 not assessed).8 With only BS3_Supporting met and no pathogenic criteria fulfilled, the evidence is insufficient to classify this variant as either likely benign or likely pathogenic; the variant remains a Variant of Uncertain Significance under the ATM VCEP framework.9

BS3 VUS
5 revelspliceai ↗bayesdel
6 vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
Gene diagram · NM_000051.4 · variants mapped to exon structure
ATM NM_000051.4
Fetching transcript structure from UCSC…
Applied criteria · 1 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= 8.92366e-05; MAF= 0.00892%, 144/1613688 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000316762; MAF= 0.03168%, 19/59982 alleles, homozygotes = 0); grpmax FAF= 0.00020684.
      v2.1
      This variant is present in gnomAD v2.1 (AF= 9.20191e-05; MAF= 0.00920%, 26/282550 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000197774; MAF= 0.01978%, 7/35394 alleles, homozygotes = 0); grpmax FAF= 9.483e-05.
      🇨🇦 CA
      This variant is absent from gnomAD-Canada.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      0.0089% · 144 / 1,613,688
      0 hom · FAF 0.021%
      Admixed American
      19 / 59,982
      0.032%
      Middle Eastern
      1 / 6,080
      0.016%
      European (non-Finnish)
      108 / 1,179,910
      0.0092%
      Remaining individuals
      5 / 62,464
      0.008%
      South Asian
      7 / 91,048
      0.0077%
      African/African American
      3 / 74,886
      0.004%
      East Asian
      1 / 44,822
      0.0022%
      + 3 not observed (European (Finnish), Amish, Ashkenazi Jewish)
      gnomAD v2.1
      0.0092% · 26 / 282,550
      0 hom · FAF 0.0095%
      Admixed American
      7 / 35,394
      0.02%
      Remaining individuals
      1 / 7,214
      0.014%
      European (non-Finnish)
      14 / 128,966
      0.011%
      South Asian
      2 / 30,612
      0.0065%
      East Asian
      1 / 19,944
      0.005%
      African/African American
      1 / 24,942
      0.004%
      + 2 not observed (Ashkenazi Jewish, European (Finnish))
      gnomAD Canada 🇨🇦
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      ClinVar screenshot
      ClinVar
      This variant has been reported in ClinVar as Uncertain significance (18 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 127327)
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.36. BayesDel score = 0.0673325.
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
      OncoKB ↗
      COSMIC screenshot
      COSMIC
      Cancer hotspots screenshot
      Cancer hotspots
      Somatic evidence Hotspot
      COSMIC
      This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53723836, n = 80 times).
      Hotspots
      This variant lies 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
      16014569 ↗ Mutations in the ATM gene lead to impaired overall and treatment-free survival that is independent of IGVH mutation status in patients with B-CLL. ONCOKB
      19781682 ↗ Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. CLINVAR
      20305132 ↗ Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study. CLINVAR
      22529920 ↗ Computational refinement of functional single nucleotide polymorphisms associated with ATM gene. CLINVAR
      23555315 ↗ Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population. 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
      26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR
      27844328 ↗ Molecular Profiling of Thymoma and Thymic Carcinoma: Genetic Differences and Potential Novel Therapeutic Targets. CLINVAR
      28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR