Variant classification summary

NM_000222.3:c.2466T>G

KIT · NP_000213.1:p.(Asn822Lys) · NM_000222.3

GRCh37: chr4:55599340 T>G · GRCh38: chr4:54733174 T>G

Gene: KIT Transcript: NM_000222.3

Final call

Likely Pathogenic

PS3 strong PM2 supporting PP3 supporting

Variant details

Gene

KIT

Transcript

NM_000222.3

Protein

NP_000213.1:p.(Asn822Lys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 strong is met because KIT N822K activates signaling and transforms Ba/F3 cells.

2

Pathogenic evidence: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.

3

Pathogenic evidence: PP3 supporting is met because REVEL 0.682 exceeds the adjudicated missense threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus two supporting pathogenic criteria yields Likely Pathogenic.

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 assessed	Not assessed: KIT N822K is reported, but no pathogenic N822K caused by a different nucleotide change is documented.	clinvar PMID:16954519 PMID:17699867 PMID:21482694
PS2	Not assessed	Not assessed: no case-specific parentage testing or confirmed de novo observation is documented for KIT c.2466T>G.	PMID:18724244
PS3	Met	Met, strong: N822K induced IL-3-independent Ba/F3 growth and KIT activation, with a PKC412 IC50 of 59 nM versus 138 nM for wild-type KIT.	PMID:15790786 PMID:16954519 PMID:17699867 PMID:21482694
PS4	Not assessed	Not assessed: no affected-versus-control counts, odds ratio, or confidence interval are available to evaluate the PS4 threshold OR > 5.0 with CI excluding 1.0.	gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: N822 is in the kinase activation loop and a hotspot, but benign variation is not excluded across the relevant region.	hotspots PMID:16954519 PMID:17699867 PMID:21482694
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to an observed allele frequency of 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 requires a recessive disorder and a pathogenic variant demonstrated in trans, neither of which is documented for this KIT variant.
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	Not assessed	Not assessed: N822Y is reported, but an independently auditable pathogenic determination for an alternate residue-822 missense variant is unavailable.	PMID:16954519 clinvar
PM6	Not assessed	Not assessed: no assumed de novo observation or parental testing result is documented for KIT c.2466T>G.	PMID:18724244
PP1	Not assessed	Not assessed: zero informative meioses or variant-positive affected relatives are documented for KIT c.2466T>G.	PMID:18724244
PP2	Not assessed	Not assessed: activating KIT missense variants are documented, but both required gene-level PP2 conditions are not established.	gnomad_v2 gnomad_v4 oncokb PMID:16954519 PMID:17699867 PMID:21482694
PP3	Met	Met at supporting strength: REVEL 0.682 meets the generic PP3 threshold of >=0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family-history details are available to determine whether the presentation is highly specific for one genetic etiology.
PP5	Not met	Not met: ClinVar has no expert-panel classification for the exact variant, and ordinary laboratory or aggregate pathogenic labels cannot trigger PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF at or above the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observed variant frequency, so no grpmax FAF exceeds the 0.01 BS1 default.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-adult observation of the exact variant is documented, and full early-age penetrance for the relevant KIT disorder is unestablished.
BS3	Not assessed	Not assessed: no validated assay shows N822K has no damaging effect; available studies instead report KIT activation and transforming cellular phenotypes.
BS4	Not assessed	Not assessed: no affected-family-member genotypes are documented to demonstrate lack of segregation for KIT c.2466T>G.	PMID:18724244
BP1	Not met	Not met: KIT disease evidence centers on recurrent activating kinase-domain missense variants, not primarily truncating variants.	oncokb PMID:16954519 PMID:17699867 PMID:21482694
BP2	Not assessed	Not assessed: no parental, offspring, pedigree, or affected-proband testing establishes KIT p.Asn822Lys in cis or trans with a pathogenic variant.
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 0.682 is above the generic BP4 supporting cutoff of <=0.29 for this missense variant.	revel
BP5	Not assessed	Not assessed: no affected case with an independently established alternate molecular basis for disease is documented.
BP6	Not met	Not met: no expert-panel benign or likely-benign classification exists for the exact variant, and ordinary ClinVar submissions cannot trigger BP6.	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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