FLT3 c.1770_1771insGCCCCAGTGACCGGCTCCTCAGATAATGAGTACTTC, p.Phe590_Tyr591insAlaProValThrGlySerSerAspAsnGluTyrPhe
NM_004119.2:c.1770_1771insGCCCCAGTGACCGGCTCCTCAGATAATGAGTACTTC
Variant of Uncertain Significance (VUS)
This in-frame FLT3 juxtamembrane insertion is absent from population databases (PM2), lies in a known mutational hotspot (PM1), and alters protein length (PM4). Computational data suggest no splicing impact (BP4). The combination of three moderate criteria supports a Likely Pathogenic classification.
ACMG/AMP Criteria Applied
PM1
PM2
PM4
BP4
Genetic Information
Gene & Transcript Details
Gene
FLT3
Transcript
NM_004119.3
MANE Select
Total Exons
24
Strand
Reverse (−)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_004119.2 | RefSeq Select | 24 exons | Reverse |
| NM_004119.1 | Alternative | 24 exons | Reverse |
Variant Details
HGVS Notation
NM_004119.2:c.1770_1771insGCCCCAGTGACCGGCTCCTCAGATAATGAGTACTTC
Protein Change
F590_Y591insAPVTGSSDNEYF
Location
Exon 14
(Exon 14 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_004119.3
Genome Browser
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HGVS InputNM_004119:c.1770_1771insGCCCCAGTGACCGGCTCCTCAGATAATGAGTACTTC
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Hotspot
PM1
Mutation Count
621
Reported mutations in this domain
050100+
Domain Summary
This variant is located in a mutational hotspot or critical domain (621 mutations).
PM1 criterion applied.
Related Variants in This Domain
Functional Summary
The FLT3 F590_Y591insAPVTGSSDNEYF variant has not been directly functionally characterized. However, similar mutations in the FLT3 juxtamembrane domain have been shown to be activating, leading to increased growth factor-independent proliferation and induction of a myeloproliferative phenotype in experimental models.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: 'Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)'. The evidence for this variant shows: it is an in‐frame insertion, not a null (LoF) variant. Therefore, this criterion is not applied because the variant does not result in a loss‐of‐function type.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: 'Same amino acid change as a known pathogenic variant but different nucleotide change'. The evidence for this variant shows: no previously established pathogenic variant at the same amino acid insertion. Therefore, this criterion is not applied because no identical amino acid change has been reported as pathogenic.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: 'De novo (both maternity and paternity confirmed) in a patient with the disease and no family history'. The evidence for this variant shows: no information on de novo occurrence or parental testing. Therefore, this criterion is not applied because de novo status is unconfirmed.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: 'Well-established functional studies supportive of a damaging effect on the gene or gene product'. The evidence for this variant shows: no direct functional studies have been performed on this specific insertion. Therefore, this criterion is not applied because functional impact has not been experimentally demonstrated for this exact variant.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: 'Prevalence in affected individuals significantly increased compared with controls'. The evidence for this variant shows: no case‐control or cohort data are available. Therefore, this criterion is not applied because statistical association data are lacking.
PM1
PM1 (Moderate)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot or well-established functional domain without benign variation'. The evidence for this variant shows: it occurs in the FLT3 juxtamembrane domain, a known hotspot for activating internal tandem duplications in AML. Therefore, this criterion is applied at Moderate strength because the variant lies in a critical functional domain known to harbor pathogenic alterations.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: 'Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: it is not present in gnomAD or other population databases. Therefore, this criterion is applied at Moderate strength because the variant is absent from large population cohorts.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant for recessive disorders'. The evidence for this variant shows: it is in a gene associated with dominant somatic activation, and no trans configuration data are available. Therefore, this criterion is not applied because PM3 pertains to autosomal recessive inheritance.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: an in-frame insertion of 14 amino acids in the protein. Therefore, this criterion is applied at Moderate strength because the variant alters protein length via an in-frame insertion.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: 'Novel missense change at an amino acid residue where a different pathogenic missense change has been seen'. The evidence for this variant shows: this is an insertion, not a missense change. Therefore, this criterion is not applied because it does not meet the missense requirement.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, but without confirmation of paternity and maternity'. The evidence for this variant shows: no data on de novo occurrence without parental confirmation. Therefore, this criterion is not applied because de novo status cannot be assumed.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Co-segregation with disease in multiple affected family members'. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied because segregation information is unavailable.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease'. The evidence for this variant shows: it is an in-frame insertion, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: 'Multiple lines of computational evidence support a deleterious effect on the gene/gene product'. The evidence for this variant shows: in silico tools (SpliceAI) predict no splicing impact and other computational data are insufficient. Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: 'Patient's phenotype or family history highly specific for a disease with a single genetic etiology'. The evidence for this variant shows: no clinical phenotype or disease context provided. Therefore, this criterion is not applied due to lack of phenotype data.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic, but without accessible evidence'. The evidence for this variant shows: no such report exists. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is too high for the disorder'. The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency is greater than expected for the disorder'. The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age'. The evidence for this variant shows: no reports in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect on protein function or splicing'. The evidence for this variant shows: no functional studies demonstrating lack of effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected family members'. The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene where only LoF causes disease'. The evidence for this variant shows: this is an in-frame insertion, not a missense variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant'. The evidence for this variant shows: no phasing data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in a repetitive region without known function'. The evidence for this variant shows: insertion is not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product'. The evidence for this variant shows: SpliceAI predicts no splicing impact and other in silico tools do not suggest deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence indicates a likely benign impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: 'Variant found in a case with an alternate molecular basis for disease'. The evidence for this variant shows: no case reports with alternate molecular diagnoses. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign, but without accessible evidence'. The evidence for this variant shows: no such reputable report. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variant with no predicted impact on splicing'. The evidence for this variant shows: it is an in-frame insertion, not a synonymous change. Therefore, this criterion is not applied.