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 applied · 15 assessed

Applied · 4

Strength Supporting Moderate Strong Very strong

✓

PS3 supporting review Pathogenic

The exact FLT3 p.(E611_F612insLAWEFPRENLE) event has a variant-specific curated OncoKB entry with Likely Gain-of-function and Likely Oncogenic annotations, and published studies of FLT3 internal tandem duplications showed constitutive activation, transforming activity, and myeloproliferative effects consistent with this established activating mechanism. In the local FLT3 framework, this supports PS3 at Supporting strength.

Variant-specific OncoKB page reported Likely Gain-of-function and Likely Oncogenic.Published FLT3 ITD studies showed constitutive activation and transforming behavior for this mutation class.

oncokb ↗PMID:11090077 ↗PMID:11756186 ↗PMID:12384447 ↗PMID:9737679 ↗

✓

PM1 moderate review Pathogenic

Mutalyzer normalized this variant to NM_004119.2:c.1835_1836ins[GGCT;1807_1835], indicating duplication of a nearby reference interval consistent with an FLT3 internal tandem duplication. The protein consequence p.(E611_F612insLAWEFPRENLE) lies in the juxtamembrane region, and published FLT3 ITD data showed that the classic activating hotspot is centered in codons 589-599. In the local FLT3 framework, a juxtamembrane ITD/activating length-mutation event in this established hotspot mechanism meets PM1_Moderate.

Normalized description showed duplicated reference sequence consistent with ITD-class event.Protein effect is a juxtamembrane in-frame insertion.FLT3 ITD hotspot literature supports this region as an established activating hotspot.

PMID:9737679 ↗PMID:11090077 ↗PMID:11756186 ↗

✓

PM2 supporting review Pathogenic

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so its observed population frequency is 0 and remains below the usual PM2 rarity threshold of 0.1%. This supports PM2 at Supporting strength.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PM5 moderate review Pathogenic

The local FLT3 framework uses a custom PM5 rule for novel in-frame internal tandem duplications and activating length mutations in the established juxtamembrane hotspot class rather than classic same-residue missense logic. This variant is an in-frame juxtamembrane ITD-class event, and published FLT3 literature has already established pathogenic/oncogenic activating length mutations in this hotspot mechanism. This supports PM5_Moderate under the local FLT3 framework.

PM5 candidate artifact flagged that this case uses a custom length-mutation PM5 mode rather than classic same-residue missense PM5.Local FLT3 framework allows PM5 for novel ITD/activating length-mutation analogues in the same hotspot class.

PMID:9737679 ↗PMID:12384447 ↗

Assessed · not applied

Pathogenic

PS2 No confirmed de novo data were identified, so PS2 cannot be assessed.

PS4 No case-control or enrichment data comparing affected and unaffected individuals were identified, so PS4 was not assessed.

PM6 No assumed de novo data without confirmed parentage were identified, so PM6 was not assessed.

PP1 No segregation data were identified, so PP1 cannot be assessed.

PP3 Computational evidence does not support a damaging splicing effect.

PP4 No specific germline phenotype or family-level clinical presentation was provided that would allow PP4 assessment.

Benign

BA1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so it does not meet the BA1 stand-alone benign frequency threshold of greater than 1%.

BS1 This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, so it does not exceed the BS1 benign frequency threshold of greater than 0.3%.

BS2 No evidence was identified showing this variant in a sufficient number of healthy adults for BS2 assessment.

BS3 Available functional evidence does not show a benign or normal effect.

BS4 No segregation data showing lack of cosegregation with disease were identified, so BS4 was not assessed.

BP2 No phase data with another pathogenic variant were identified, so BP2 was not assessed.

BP3 BP3 should not be applied to FLT3 juxtamembrane internal tandem duplication or activating length-mutation events because this region has a known activating disease mechanism and recurrent pathogenic/oncogenic variation.

BP4 SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.09, but this does not provide benign support for an in-frame juxtamembrane FLT3 insertion with an established activating protein-level mechanism.

BP5 No alternate molecular explanation for a reported phenotype was identified, so BP5 was not assessed.

N/A · 9 PVS1 · PS1 · PM3 · PM4 · PP2 · PP5 · BP1 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

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

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

SpliceAI ↗

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

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

Re-run this variant?