Variant classification summary

NM_004119.2:c.2515G>A

FLT3 · NP_004110.2:p.(Asp839Asn) · NM_004119.2

GRCh37: chr13:28592630 C>T · GRCh38: chr13:28018493 C>T

Gene: FLT3 Transcript: NM_004119.2

Final call

VUS

PM2 supporting

Variant details

Gene

FLT3

Transcript

NM_004119.2

Protein

NP_004110.2:p.(Asp839Asn)

gnomAD AF

6.195748477394811e-07 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, with only 1/1,614,010 alleles (AF 6.2e-07) in gnomAD v4.1, below the <0.1% rare-frequency threshold.

2

Overall classification: VUS — the single Supporting criterion (PM2) does not satisfy any ACMG/AMP 2015 pathogenic or benign combination rule.

Final determination:

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: missense substitution with no null-variant mechanism (nonsense, frameshift, or canonical splice disruption).	pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	Not assessed: insufficient evidence was available to establish a known pathogenic change at the same residue.
PS2	Not assessed	Not assessed: no parental testing or de novo evidence was documented.
PS3	Not met	Not met: no variant-specific functional assay evidence exists for p.Asp839Asn, and OncoKB returned no reviewed functional data for this exact change.	oncokb vcep_flt3_oncokb_guidance vcep_flt3_itd_hotspot_and_function
PS4	Not assessed	Not assessed: no case-control or cohort enrichment data for this variant were available.	clinvar gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM1	Not assessed	Not assessed: insufficient evidence was available to evaluate a protein domain or mutational hotspot.
PM2	Met	Met (Supporting): absent from gnomAD v2.1 and gnomAD-Canada v1.0, with only 1/1,614,010 alleles in gnomAD v4.1, below the <0.1% rare-frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence of a second pathogenic variant in trans or a recessive-disease context was available.
PM4	N/A	Not applicable: missense substitution with no change to protein length.	pvs1_variant_assessment
PM5	Not assessed	Not assessed: insufficient evidence was available to evaluate a pathogenic change at the same residue.
PM6	Not assessed	Not assessed: no de novo observation with unconfirmed parentage was documented.
PP1	Not assessed	Not assessed: no family segregation or cosegregation data were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate the gene's burden of missense variation.
PP3	Not met	Not met: REVEL 0.481 falls in the indeterminate zone below the 0.644 supporting-pathogenic threshold.	spliceai revel
PP4	Not assessed	Not assessed: no proband phenotype, family history, or tumor phenotype was available to support a single-gene etiology.	clinvar
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic or Likely pathogenic classification exists for this exact variant.	clinvar oncokb
BA1	Not met	Not met: gnomAD v4.1 AF 6.19575e-07 (1/1,614,010 alleles) is far below the >1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: the highest observed population AF is 1.60051e-05, far below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes for this variant.	gnomad_v4 gnomad_v2 gnomad_canada
BS3	Not met	Not met: no functional study of this variant was identified to demonstrate a benign effect.	oncokb
BS4	Not assessed	Not assessed: no unaffected relatives tested for the variant were documented.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant's effect on a non-canonical transcript.
BP2	Not assessed	Not assessed: no genotype or cis/trans phase data were available.
BP3	N/A	Not applicable: missense substitution, not an in-frame indel in a repetitive region.	pvs1_variant_assessment
BP4	Not met	Not met: REVEL 0.481 is above the 0.290 benign-supporting threshold, so it does not support benignity.	spliceai revel
BP5	Not assessed	Not assessed: no evidence of an alternate molecular cause explaining a phenotype was available.	clinvar
BP6	Not met	Not met: no ClinVar expert-panel Benign or Likely benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: missense substitution, not a synonymous variant.

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