Starting
Initialising…
0%
FLT3
Final classification
Likely Pathogenic
FLT3 c.1835_1836insGGCTTGGGAGTTTCCAAGAGAAAATTTAGAGTT · p.Glu611_Phe612insLeuAlaTrpGluPheProArgGluAsnLeuGlu
FLT3

The FLT3 c.1835_1836insGGCTTGGGAGTTTCCAAGAGAAAATTTAGAGTT (p.(E611_F612insLAWEFPRENLE)) variant has not been reported in ClinVar.

Gene
FLT3
Transcript
NM_004119.2
HGVS · transcript:coding
NM_004119.2:c.1835_1836insGGCTTGGGAGTTTCCAAGAGAAAATTTAGAGTT
Consequence
N/A
GRCh38
chr13:28034083 A>AAACTCTAAATTTTCTCTTGGAAACTCCCAAGCC
GRCh37
chr13:28608220 A>AAACTCTAAATTTTCTCTTGGAAACTCCCAAGCC
Basis Local FLT3 ITD / activating length-mutation framework (local-flt3-itd-framework-v1), which uses ACMG/AMP 2015 final category thresholds with custom FLT3 criterion specifications. ▾
Local FLT3 ITD / activating length-mutation framework (local-flt3-itd-framework-v1), which uses ACMG/AMP 2015 final category thresholds with custom FLT3 criterion specifications.
Classification rationale
PS3PM1PM2PM5 Likely Pathogenic
FLT3 c.1835_1836insGGCTTGGGAGTTTCCAAGAGAAAATTTAGAGTT

The FLT3 c.1835_1836insGGCTTGGGAGTTTCCAAGAGAAAATTTAGAGTT (p.(E611_F612insLAWEFPRENLE)) variant has not been reported in ClinVar.1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.2 Mutalyzer normalization is consistent with an FLT3 internal tandem duplication, and published studies of FLT3 internal tandem duplications showed constitutive activation, transforming activity, and myeloproliferative effects; the exact p.(E611_F612insLAWEFPRENLE) event also has variant-specific curated evidence consistent with likely gain of function.3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.09.4

PS3 + PM1 + PM2 + PM5 → Likely Pathogenic
1 clinvar ↗
2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
3 oncokb ↗PMID:11090077 ↗PMID:11756186 ↗PMID:12384447 ↗PMID:9737679 ↗vcep_flt3_itd_hotspot_and_functionvcep_flt3_oncokb_guidance
4 spliceai ↗
Gene diagram · NM_004119.2 · variants mapped to exon structure
FLT3 NM_004119.2
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 pathogenic
      gnomAD v4.1 screenshot
      gnomAD v4.1
      gnomAD v2.1 screenshot
      gnomAD v2.1
      v4.1
      Absent from gnomAD v4.1.
      v2.1
      Absent from gnomAD v2.1.
      🇨🇦 CA
      Absent from gnomAD-Canada v1.0.
      Allele frequency by ancestry
      three datasets · side by side
      gnomAD v4.1
      Absent · 0 / ?
      0 hom
      Not observed in any ancestry group.
      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.
      gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
      ClinVar screenshot
      ClinVar
      This variant is absent from ClinVar.
      ClinVar ↗
      SpliceAI screenshot
      In silico
      SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
      SpliceAI ↗
      Functional / OncoKB screenshot
      Functional Likely Oncogenic
      OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
      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.
      COSMIC ↗ Hotspots ↗
      Literature · how each cited paper was used
      4papers cited
      Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.
      PMID PMID:11090077
      PMID PMID:11090077 ↗
      Found
      Structured finding pending for this record — see source link.
      Applied to
      →PM1 supports · met →PS3 supports · met
      PMID PMID:11756186
      PMID PMID:11756186 ↗
      Found
      Structured finding pending for this record — see source link.
      Applied to
      →PM1 supports · met →PS3 supports · met
      PMID PMID:12384447
      PMID PMID:12384447 ↗
      Found
      Structured finding pending for this record — see source link.
      Applied to
      →PM5 supports · met →PS3 supports · met
      PMID PMID:9737679
      PMID PMID:9737679 ↗
      Found
      Structured finding pending for this record — see source link.
      Applied to
      →PM1 supports · met →PM5 supports · met →PS3 supports · met
      Sources & reference links
      8Sources
      ClinVar
      gnomAD v2.1
      gnomAD v4.1
      gnomAD-Canada
      SpliceAI
      OncoKB
      COSMIC
      Cancer hotspots
      Triaged references · 6 PMIDs not cited in assessment
      11090077 ↗ Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. ONCOKB
      11756186 ↗ FLT3 internal tandem duplication mutations associated with human acute myeloid leukemias induce myeloproliferative disease in a murine bone marrow transplant model. ONCOKB
      12384447 ↗ A new and recurrent activating length mutation in exon 20 of the FLT3 gene in acute myeloid leukemia. ONCOKB
      23631653 ↗ FLT3 tyrosine kinase inhibitors in acute myeloid leukemia: clinical implications and limitations. ONCOKB
      26438511 ↗ Profiling of somatic mutations in acute myeloid leukemia with FLT3-ITD at diagnosis and relapse. ONCOKB
      9737679 ↗ Internal tandem duplication of the FLT3 gene is a novel modality of elongation mutation which causes constitutive activation of the product. ONCOKB