LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-07
Case ID: NM_000222.3_c.2009C_T_20261107_001744
Framework: ACMG/AMP 2015
Variant classification summary

NM_000222.3:c.2009C>T

KIT  · NP_000213.1:p.(Thr670Ile)  · NM_000222.3
GRCh37: chr4:55595519 C>T  ·  GRCh38: chr4:54729353 C>T
Gene: KIT Transcript: NM_000222.3
Final call
Likely Pathogenic
PS3 strong PM1 moderate PM2 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.(Thr670Ile)
gnomAD AF
1.8591553485420504e-06 (v4.1)
ClinVar
Uncertain significance
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Pathogenic: PS3 strong is met by concordant variant-specific cellular and biochemical evidence of altered KIT function and imatinib resistance.
2
Likely Pathogenic: PM1 moderate is met because T670 is an established KIT kinase ATP-binding-pocket gatekeeper residue.
3
Likely Pathogenic: PM2 supporting is met because the gnomAD v4.1 maximum group FAF is 5.53e-06 with zero homozygotes.
4
Likely Pathogenic: PP3 moderate is met because REVEL 0.895 exceeds the calibrated moderate threshold.
Final determination: Under the generic ACMG/AMP 2015 fallback, one strong pathogenic criterion plus one or two moderate pathogenic criteria supports Likely Pathogenic; the applied combination is PS3 strong, PM1 moderate, PP3 moderate, and PM2 supporting.
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: KIT p.Thr670Ile is reported, but the exact variant is ClinVar uncertain significance rather than a previously established pathogenic variant.
clinvar PMID:16751810 PMID:15685537 PMID:16954519 PMID:27527414
PS2 Not assessed Not assessed: no documented proband phenotype, family-history assessment, or confirmed maternity and paternity is available for this variant.
clinvar
PS3 Met Met at strong: independent cellular and biochemical assays consistently show KIT T670I phosphorylation, altered kinase activity, and imatinib resistance across multiple models.
PMID:16751810 PMID:15685537 PMID:16954519 PMID:27527414 PMID:17545544
PS4 Not assessed Not assessed: available reports describe somatic T670I in treated GIST tumors but provide no valid matched germline case-control comparison with an OR/RR and 95% CI.
PMID:15685537 PMID:16954519 gnomad_v4
PM1 Met Met at moderate strength: T670 is an established KIT kinase ATP-binding-pocket gatekeeper, and the variant has gnomAD v4.1 AF 1.85916e-06.
PMID:16751810 PMID:16954519 PMID:27527414 gnomad_v4
PM2 Met Met at supporting strength: gnomAD v4.1 grpmax FAF is 5.53e-06, below the <=0.0001 PM2 threshold, with zero homozygotes.
gnomad_v4 gnomad_v2 generic_acmg_combination_rules
PM3 Not assessed Not assessed: no germline trans observation or parental/offspring phase testing is documented for the KIT variant.
PMID:15685537 PMID:16954519
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 met Not met: the evidence reports T670I itself but no different missense change at residue 670 established as pathogenic.
PMID:15685537 PMID:16751810 PMID:16954519 PMID:27527414 pm5_candidates
PM6 Not assessed Not assessed: germline submission records do not establish an assumed de novo occurrence or provide parental testing and phenotype details.
clinvar
PP1 Not assessed Not assessed: no affected relatives, informative meioses, or genotype-phenotype co-segregation data are reported for the germline variant.
clinvar PMID:15685537 PMID:16751810 PMID:16954519
PP2 Not assessed Not assessed: the required KIT-wide benign-missense rate and inherited missense-disease mechanism are not established by the supplied evidence.
PP3 Met Met at moderate strength: REVEL 0.895 meets the PP3 moderate threshold of >= 0.773 for this missense variant.
revel
PP4 Not assessed Not assessed: no patient phenotype or family history establishing a highly specific single-gene disease presentation is available.
PP5 Not met Not met: ClinVar has two exact-variant laboratory submissions, both uncertain significance, and zero expert-panel pathogenic classifications.
clinvar
BA1 Not met Not met: gnomAD v4.1 grpmax FAF is 5.53e-06, far below the 0.05 BA1 threshold.
gnomad_v4 generic_acmg_combination_rules
BS1 Not met Not met: gnomAD v4.1 grpmax FAF is 5.53e-06, below the generic 0.01 BS1 threshold.
gnomad_v4 gnomad_v2 generic_acmg_combination_rules
BS2 Not assessed Not assessed: no healthy-adult observation or established early-onset, fully penetrant germline disorder context is available.
BS3 Not met Not met: all five variant-specific functional studies report altered KIT activity or drug resistance, not absence of a damaging effect.
PMID:16751810 PMID:15685537 PMID:16954519 PMID:27527414 PMID:17545544
BS4 Not assessed Not assessed: no affected relatives with negative variant testing or other documented non-segregation evidence is available.
clinvar
BP1 Not assessed Not assessed: no validated evidence shows that the relevant KIT disease is caused primarily by truncating variants.
BP2 Not assessed Not assessed: no germline cis phase or fully penetrant dominant-disorder trans observation is documented for the KIT variant.
PMID:15685537 PMID:16954519
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 0.895 exceeds the BP4 supporting threshold of <= 0.29, so the missense result is gray-zone rather than benign.
revel
BP5 Not met Not met: T670I co-occurred with a primary KIT tumor alteration in resistant GIST, not a documented constitutional disease case with an alternate basis.
PMID:15685537
BP6 Not met Not met: ClinVar contains no exact-variant expert-panel benign classification, and both available laboratory submissions call the variant uncertain significance.
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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