Variant classification summary

NM_004119.3:c.2503G>T

FLT3 · NP_004110.2:p.(Asp835Tyr) · NM_004119.3

GRCh37: chr13:28592642 C>A · GRCh38: chr13:28018505 C>A

Gene: FLT3 Transcript: NM_004119.3

Final call

Pathogenic

PS3 strong PM1 moderate PP3 moderate PM2 supporting

Variant details

Gene

FLT3

Transcript

NM_004119.3

Protein

NP_004110.2:p.(Asp835Tyr)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 Strong is supported by concordant cellular and in vivo evidence of constitutive FLT3 activation.

2

Pathogenic: PM1 Moderate is supported by the recurrent D835 activation-loop hotspot and absence of observed benign population variation.

3

Pathogenic: PP3 Moderate is supported by REVEL 0.875, above the 0.773 moderate threshold.

4

Pathogenic: PM2 Supporting is supported by absence from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 rules, one Strong plus two Moderate plus at least two Supporting pathogenic criteria yields Pathogenic, and no benign rule is satisfied.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.2503G>T is a missense substitution producing p.Asp835Tyr, not one of the specified null-variant classes required for PVS1.	pvs1_generic_framework
PS1	Not assessed	Not assessed: no independently established pathogenic alternate nucleotide change producing the same FLT3 p.D835Y amino-acid substitution was identified.
PS2	Not assessed	Not assessed: no proband-level de novo result with both confirmed maternity and paternity is documented.
PS3	Met	Met at strong strength: four variant-specific studies demonstrate constitutive FLT3 activation, abnormal cellular signaling or growth, and an in vivo D835Y phenotype.	PMID:11290608 PMID:15256420 PMID:24255108 PMID:26108694 oncokb vcep_flt3_itd_hotspot_and_function vcep_flt3_oncokb_guidance
PS4	Not met	Not met: D835Y enrichment gave OR 9.68 > 5.0, but the continuity-corrected 95% CI was 0.53-177.75 and included 1.0.	PMID:11442493
PM1	Met	Met at moderate strength: p.D835Y lies in the recurrent FLT3 activation-loop hotspot, and it is absent from gnomAD v2.1, v4.1, and Canada.	PMID:11290608 PMID:24255108 PMID:26108694 gnomad_v2 gnomad_v4 gnomad_canada
PM2	Met	Met at Supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the variant is documented in somatic leukemia, with no recessive disorder or biallelic in-trans observation established.	clinvar PMID:11290608
PM4	N/A	Not applicable: p.Asp835Tyr changes one amino acid without an in-frame insertion, deletion, stop-loss event, or protein-length change required for PM4.	vcep_flt3_itd_hotspot_and_function
PM5	Not assessed	Not assessed: alternate D835 substitutions were studied functionally, but none was established as pathogenic in the available evidence for classic missense PM5.	PMID:11290608 PMID:15256420
PM6	Not assessed	Not assessed: no assumed de novo occurrence without parental confirmation is documented for this proband.
PP1	Not assessed	Not assessed: zero informative affected-relative meioses or segregation results are documented for this family.
PP2	Not met	Not met: FLT3 missense activation is established, but no validated evidence demonstrates the required low rate of benign missense variation.	PMID:11290608 PMID:24255108
PP3	Met	Met at moderate strength: REVEL 0.875 meets the PP3 moderate threshold of >=0.773 but not the strong threshold of >=0.932.	revel
PP4	Not met	Not met: AML and ALL are not highly specific phenotypes for a single genetic etiology, so the PP4 specificity requirement is not satisfied.	PMID:11442493 clinvar
PP5	Not met	Not met: ClinVar lists Pathogenic without an expert-panel classification or assertion criteria, so the exact-variant PP5 requirement is absent.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, far below the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4 clinvar
BS1	Not met	Not met: no gnomAD allele was observed, so no filtering AF reaches the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carrier or homozygote observation is available for the required penetrance and age context.
BS3	Not met	Not met: variant-specific assays consistently show constitutive FLT3 activation and abnormal cellular or mouse phenotypes rather than preserved protein function.	PMID:11290608 PMID:15256420 PMID:24255108 PMID:26108694 vcep_flt3_itd_hotspot_and_function vcep_flt3_oncokb_guidance
BS4	Not assessed	Not assessed: no affected family members with documented negative variant testing are available to demonstrate non-segregation.
BP1	Not met	Not met: FLT3 disease-associated variation prominently includes recurrent activating kinase-domain missense substitutions, not primarily truncating variants.	PMID:11290608 PMID:24255108 PMID:26108694
BP2	Not assessed	Not assessed: no parental, offspring, haplotyping, or other phase-resolved observation establishes a pathogenic variant in cis or in trans.
BP3	N/A	Not applicable: c.2503G>T is a missense SNV, not an in-frame deletion or insertion in a repetitive region as required for BP3.	vcep_flt3_itd_hotspot_and_function
BP4	Not met	Not met: REVEL 0.875 exceeds the BP4 supporting threshold of <=0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no sufficiently characterized case record shows an alternate molecular basis for the patient’s disease.
BP6	Not met	Not met: ClinVar reports Pathogenic with zero expert-panel submissions and provides no exact-variant expert-panel benign classification.	clinvar
BP7	N/A	Not applicable: this is a missense substitution producing p.Asp835Tyr, whereas BP7 is restricted to synonymous variants.

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