LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-28
Case ID: NM_000222.3_c.2447A_T_20261028_051516
Framework: ACMG/AMP 2015
Variant classification summary

NM_000222.3:c.2447A>T

KIT  · NP_000213.1:p.(Asp816Val)  · NM_000222.3
GRCh37: chr4:55599321 A>T  ·  GRCh38: chr4:54733155 A>T
Gene: KIT Transcript: NM_000222.3
Final call
Pathogenic
PS3 strong PM1 moderate PM5 moderate PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
KIT
Transcript
NM_000222.3
Protein
NP_000213.1:p.(Asp816Val)
gnomAD AF
1.860033703810713e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong is supported by independent cellular and in vivo assays showing constitutive KIT D816V activation and abnormal proliferation.
2
Pathogenic: PM1 moderate is supported because p.Asp816Val lies in the KIT activation-loop hotspot.
3
Pathogenic: PM5 moderate is supported by the disease-associated activating alternate missense p.Asp816Tyr at the same residue.
4
Pathogenic: PM2 supporting is supported by the very low gnomAD v4.1 allele frequency of 1.86003e-06.
5
Pathogenic: PP3 supporting is supported by REVEL 0.89 exceeding the generic missense threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, 1 strong pathogenic criterion plus 2 moderate and 2 supporting pathogenic criteria supports a Pathogenic call.
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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not met Not met: no distinct nucleotide substitution producing KIT p.Asp816Val was documented beyond the observed c.2447A>T change.
clinvar PMID:15790786
PS2 Not assessed Not assessed: a de novo assertion is present, but confirmed maternity and paternity, parental testing, and family-history details are undocumented.
clinvar
PS3 Met Met, strong: independent cell and mouse assays show KIT D816V constitutive activation, IL-3-independent growth, increased STAT5 signaling, and mastocytosis-like disease.
PMID:15790786 PMID:10362788 PMID:16352739 PMID:19893034 PMID:12569358 PMID:14645423 PMID:15972446
PS4 Not assessed Not assessed: affected-case and control counts needed to calculate OR and 95% CI against the >5.0 and CI-not-including-1.0 threshold are unavailable.
PMID:12569358 PMID:16352739 PMID:19893034 PMID:15725473 PMID:15972446 gnomad_v4
PM1 Met Met, moderate: KIT D816V is in the activation-loop hotspot, with 3/1,612,874 gnomAD v4.1 alleles and zero homozygotes.
PMID:15790786 gnomad_v4
PM2 Met Met at supporting: gnomAD v4.1 frequency is 1.86003e-06, below the <=0.0001 PM2 threshold, with 0 homozygotes.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: inheritance pattern, parental phase, and a pathogenic variant in trans are not documented for this KIT c.2447A>T case.
PM4 N/A Not applicable: PM4 requires a protein-length change, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Met Met, moderate: the alternate same-residue missense p.Asp816Tyr is reported as a common activating KIT mutation in disease contexts.
PMID:15790786 PMID:10362788
PM6 Not assessed Not assessed: one ClinVar assertion suggests de novo occurrence, but primary case documentation and parental testing details are unavailable.
clinvar
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or family-level cosegregation data are reported for the variant.
PP2 Not assessed Not assessed: no gene-wide benign-missense rate and applicable missense-mechanism evidence were supplied for KIT.
PP3 Met Met at supporting: REVEL 0.89 exceeds the generic PP3 supporting threshold of 0.644 for this missense variant.
revel
PP4 Not assessed Not assessed: the current patient's phenotype and family history, required to judge highly specific disease presentation, are not provided.
PP5 Not met Not met: ClinVar has zero expert-panel submissions for this exact variant, so no qualifying expert-panel pathogenic assertion supports PP5.
clinvar
BA1 Not met Not met: gnomAD v4.1 all-comers frequency is 1.86003e-06, below the >=0.05 BA1 threshold.
gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v4.1 frequency is 1.86003e-06, far below the generic >=0.01 BS1 threshold.
gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: gnomAD reports 0 homozygotes but does not document a healthy adult carrier with the required zygosity and penetrance context.
gnomad_v2 gnomad_v4
BS3 Not met Not met: variant-specific assays show constitutive KIT signaling, growth-factor-independent proliferation, and mastocytosis-like disease rather than preserved function.
PMID:15790786 PMID:10362788 PMID:16352739 PMID:19893034 PMID:12569358 PMID:14645423 PMID:15972446
BS4 Not assessed Not assessed: no affected relatives without the variant or family-testing results are documented to demonstrate lack of segregation.
BP1 Not met Not met: KIT is characterized by recurrent activating missense mutations, not a primarily truncating disease mechanism.
oncokb PMID:15790786
BP2 Not assessed Not assessed: no pathogenic variant and no verified cis or trans phase relationship are documented for KIT c.2447A>T.
BP3 N/A Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.89 is above the generic BP4 supporting cutoff of 0.29 for this missense variant.
revel
BP5 Not assessed Not assessed: no case-level alternate molecular basis for the disease is documented alongside this variant.
BP6 Not met Not met: no exact-variant ClinVar expert-panel benign or likely benign classification is present.
clinvar
BP7 N/A Not applicable: BP7 requires a synonymous variant, and this is a missense variant.
generic_acmg_combination_rules
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