LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-03
Case ID: NM_000222.3_c.1924A_G_20261103_021541
Framework: ACMG/AMP 2015
Variant classification summary

NM_000222.3:c.1924A>G

KIT  · NP_000213.1:p.(Lys642Glu)  · NM_000222.3
GRCh37: chr4:55594221 A>G  ·  GRCh38: chr4:54728055 A>G
Gene: KIT Transcript: NM_000222.3
Final call
Pathogenic
PS3 strong PM1 moderate PM2 supporting PP1 supporting PP3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
KIT
Transcript
NM_000222.3
Protein
NP_000213.1:p.(Lys642Glu)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS3 strong is supported by concordant activating and tumorigenic functional effects for p.Lys642Glu.
2
Pathogenic: PM1 moderate places Lys642 in KIT's critical kinase domain I.
3
Pathogenic: PM2 supporting reflects absence from the searched gnomAD datasets.
4
Pathogenic: PP1 supporting reflects cosegregation across three familial GIST kindreds.
5
Pathogenic: PP3 moderate reflects REVEL 0.908 exceeding the 0.773 threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, 1 Strong + 2 Moderate + 2 Supporting pathogenic criteria yields 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 met Not met: p.Lys642Glu is established as pathogenic, but no distinct nucleotide change producing the same amino-acid substitution was identified.
clinvar PMID:11073817 PMID:23648119
PS2 Not assessed Not assessed: no proband-specific confirmed maternity and paternity testing or de novo status is reported for this familial germline KIT variant.
PMID:23648119 PMID:11073817
PS3 Met Met, strong: two independent assays showed constitutive KIT activation, autonomous cell growth, and nude-mouse tumor formation for the exact K642E variant.
PMID:11073817 PMID:11526490
PS4 Not assessed Not assessed: affected-family reports lack unaffected-control counts, so no odds ratio or 95% confidence interval can be calculated against the OR >5.0 threshold.
PMID:11073817 PMID:23648119
PM1 Met Met: Lys642 lies in KIT kinase domain I, and the variant is absent from both gnomAD v2.1 and v4.1.
gnomad_v2 gnomad_v4 PMID:11073817 PMID:11526490
PM2 Met Met at supporting: the variant is absent from gnomAD v2.1, v4.1, and both available non-cancer searches, giving observed frequency 0 versus the <=0.0001 threshold.
gnomad_v2 gnomad_v4
PM3 Not assessed Not assessed: the reports show a germline heterozygous variant in an affected mother and son, but no second pathogenic allele in trans or phase testing.
PMID:11073817 PMID:23648119
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: no different pathogenic missense substitution at KIT Lys642 was established in the available evidence.
pm5_candidates clinvar
PM6 Not assessed Not assessed: the available reports describe familial KIT transmission, not an assumed de novo variant without parental confirmation.
PMID:23648119 PMID:11073817
PP1 Met Met at supporting: the same variant was present in all patients across three families, including 20 affected patients, with additional mother-son familial transmission.
PMID:23648119 PMID:11073817
PP2 Not assessed Not assessed: KIT missense activation is supported, but no gene-wide low benign-missense-rate metric was provided.
gnomad_v2 gnomad_v4 PMID:11073817 PMID:11526490
PP3 Met Met at moderate strength: REVEL 0.908 exceeds the moderate PP3 threshold of 0.773 for this missense variant.
revel
PP4 Not met Not met: familial GIST is documented, but GIST is not highly specific for a disease with a single genetic etiology under generic PP4.
PMID:11073817 PMID:23648119
PP5 Not met Not met: exact-variant ClinVar records contain zero expert-panel submissions, so non-expert Pathogenic assertions cannot trigger PP5.
clinvar
BA1 Not met Not met: the variant is absent from gnomAD v2.1 and v4.1, with no observed frequency meeting the 0.05 BA1 threshold.
gnomad_v2 gnomad_v4
BS1 Not met Not met: gnomAD v2.1 and v4.1 show no observed allele frequency, so the 0.01 BS1 default is not reached.
gnomad_v2 gnomad_v4
BS2 Not assessed Not assessed: available reports describe affected germline carriers but do not document a qualifying healthy adult carrying the variant.
PMID:11073817 PMID:23648119
BS3 Not met Not met: available functional studies show constitutive KIT activation, autonomous growth, and tumor formation rather than no damaging effect.
PMID:11073817 PMID:11526490
BS4 Not assessed Not assessed: no affected family member is documented as a tested noncarrier, so lack of segregation cannot be established.
PMID:23648119 PMID:11073817
BP1 Not met Not met: familial KIT disease evidence centers on activating missense p.Lys642Glu, not primarily truncating variants.
PMID:11073817 PMID:23648119
BP2 Not assessed Not assessed: familial observations document the KIT variant but provide no second pathogenic variant and no cis/trans phase result.
PMID:11073817 PMID:23648119
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 0.908 is above the most permissive supporting BP4 threshold of 0.29 for this missense variant.
revel
BP5 Not assessed Not assessed: reviewed reports do not document an independent alternate molecular basis for the disease in a variant-positive case.
PMID:23940219 PMID:24855380
BP6 Not met Not met: no exact-variant benign expert-panel report exists, and ClinVar reports zero expert-panel submissions for this variant.
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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