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

VUS

PM2 supporting PP3 moderate

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 evidence: PM2 supporting reflects the variant's absence from gnomAD v2.1 and v4.1.

2

Pathogenic evidence: PP3 moderate is supported by REVEL 0.875 meeting the moderate threshold.

Final determination: Under the local FLT3 framework's ACMG/AMP combination rules, one moderate and one supporting pathogenic criterion do not satisfy a pathogenic or likely pathogenic rule, and no benign rule is satisfied; therefore the call is VUS.

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 p.Asp835Tyr substitution, not one of the null-variant classes eligible for generic PVS1.	pvs1_generic_framework
PS1	Not met	Not met: reviewed reports document D835Y itself, but no different nucleotide change producing the same Asp835Tyr amino-acid substitution was identified.	PMID:11442493 PMID:15256420
PS2	Not assessed	Not assessed: no confirmed maternity and paternity, family-history assessment, or germline de novo testing is documented for the proband.	PMID:11442493
PS3	N/A	Not applicable: the local PS3 rule is limited to exact FLT3 ITD or activating length-mutation variants, whereas this variant is the missense substitution p.D835Y.	vcep_flt3_itd_hotspot_and_function vcep_flt3_oncokb_guidance oncokb PMID:15256420 PMID:24255108 PMID:26108694
PS4	Not met	Not met: corrected OR 9.57 exceeds 5, but the 95% CI 0.52-175.81 includes 1.0.	PMID:11442493
PM1	N/A	Not applicable: the FLT3 PM1 rule covers juxtamembrane ITD or length-mutation events at codons 589-599, whereas this is an activation-loop missense substitution at residue 835.	vcep_flt3_itd_hotspot_and_function
PM2	Met	Met at Supporting: the variant was absent from gnomAD v2.1 and v4.1, consistent with allele frequency 0 versus 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 affected-proband compound-heterozygous observation established.	PMID:11442493 clinvar
PM4	N/A	Not applicable: p.Asp835Tyr is a missense substitution with no protein-length change, while local PM4 is limited to distinct FLT3 length-change events.	vcep_flt3_itd_hotspot_and_function
PM5	N/A	Not applicable: custom FLT3 PM5 is restricted to novel juxtamembrane ITD or activating length mutations at the codons 589-599 hotspot, not p.Asp835Tyr missense substitutions.	vcep_flt3_itd_hotspot_and_function vcep_flt3_oncokb_guidance
PM6	Not assessed	Not assessed: the reported AML observation is somatic, with no documented germline de novo event lacking parental confirmation.	PMID:11442493
PP1	Not assessed	Not assessed: zero affected relatives or informative meioses are reported for this variant in a familial segregation study.	PMID:11442493
PP2	Not assessed	Not assessed: activating FLT3 missense disease evidence is available, but the required gene-level rate of benign missense variation is not provided.	PMID:11442493 PMID:15256420
PP3	Met	Met at moderate: REVEL 0.875 meets the PP3 moderate threshold of >=0.773 but does not reach the strong threshold of >=0.932.	revel
PP4	Not assessed	Not assessed: no individual patient phenotype or family history specific enough to evaluate the PP4 requirement is available.
PP5	Not met	Not met: ClinVar shows Pathogenic without an exact-variant expert-panel classification, so the PP5 gate is not satisfied.	clinvar
BA1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, far below the >=0.05 BA1 allele-frequency threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant was absent from gnomAD v2.1 and v4.1, with no allele frequency exceeding the generic 0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult germline carrier observation or established full-penetrance early-onset disorder model is documented for this somatic variant.	gnomad_v2 gnomad_v4 clinvar
BS3	Not met	Not met: D835Y showed constitutive FLT3 activation, factor-independent proliferation, and a myeloproliferative phenotype, not the no-damaging-effect required for BS3.	generic_acmg_combination_rules PMID:15256420 PMID:24255108 PMID:26108694
BS4	Not assessed	Not assessed: no affected family members were tested, so lack of segregation cannot be demonstrated.	PMID:11442493
BP1	Not assessed	Not assessed: FLT3 activating missense evidence is documented, but no comprehensive gene-level evidence shows whether disease-causing variants are primarily truncating.	PMID:11442493 PMID:15256420
BP2	Not assessed	Not assessed: no phase data show the variant in trans or cis with a pathogenic variant, and available reports are somatic leukemia observations.	PMID:11442493 PMID:15256420 PMID:24255108 clinvar
BP3	N/A	Not applicable: p.Asp835Tyr is not an in-frame ITD or activating length mutation, the only variant class covered by local FLT3 BP3.	vcep_flt3_itd_hotspot_and_function
BP4	Not met	Not met: REVEL 0.875 exceeds the BP4 supporting threshold of <=0.29, so the missense variant is not in the benign prediction range.	revel
BP5	Not assessed	Not assessed: no documented alternate molecular basis for disease is reported in the available case evidence.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel classification reports this variant as benign or likely benign.	clinvar
BP7	N/A	Not applicable: the variant is missense, p.(Asp835Tyr), whereas BP7 applies only to synonymous variants.

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