Variant classification summary

NM_000222.3:c.1961T>C

KIT · NP_000213.1:p.(Val654Ala) · NM_000222.3

GRCh37: chr4:55594258 T>C · GRCh38: chr4:54728092 T>C

Gene: KIT Transcript: NM_000222.3

Final call

VUS

PS3 supporting PM2 supporting PP3 moderate

Variant details

Gene

KIT

Transcript

NM_000222.3

Protein

NP_000213.1:p.(Val654Ala)

gnomAD AF

6.197046239880223e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 supporting: a controlled KIT V654A cellular assay showed altered receptor activity and imatinib resistance.

2

PM2 supporting: gnomAD v4.1 allele frequency is 6.197046239880223e-07 with zero homozygotes.

3

PP3 moderate: REVEL 0.82 meets the supplied moderate deleteriousness threshold.

4

VUS: one moderate and two supporting criteria satisfy no generic ACMG/AMP pathogenic or benign rule.

Final determination: Under the generic ACMG/AMP 2015 fallback, one moderate plus two supporting criteria does not meet any pathogenic, likely pathogenic, benign, or likely benign combination, so 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: 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: p.Val654Ala is reported, but no previously established pathogenic record for the same amino-acid change is available.	PMID:16751810 PMID:18623623 clinvar
PS2	Not assessed	Not assessed: no documented proband phenotype, family history, or confirmed maternity and paternity testing is available.
PS3	Met	Met at supporting strength: KIT V654A retained phosphorylation at 3 micromolar imatinib but was inhibited at 6 micromolar in a controlled variant-specific cellular assay.	PMID:16751810
PS4	Not met	Not met: no affected-versus-control counts or OR/RR were reported, and the available 27% treatment-resistance cohort lacks controls for the PS4 threshold.	PMID:18623623
PM1	Not assessed	Not assessed: V654 lies in the ATP-binding kinase domain, but absence of benign variation in that domain is not established.	PMID:16751810 gnomad_v4 hotspots
PM2	Met	Met at supporting strength: gnomAD v4.1 AF is 6.197046239880223e-07, below the <=0.0001 PM2 threshold, with zero homozygotes.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no parent or offspring phase testing, affected-proband observation, or documented pathogenic variant in trans is available for this variant.	clinvar PMID:18623623
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: no different pathogenic missense substitution at KIT residue 654 is documented in the reviewed evidence.	PMID:16751810 PMID:18623623 pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo occurrence, affected proband context, or parental testing result is documented.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or cosegregation results are documented.
PP2	Not assessed	Not assessed: recurrent activating KIT missense variants are reported, but no validated low-benign-missense rate is available.	PMID:16751810 oncokb gnomad_v4
PP3	Met	Met at moderate strength: missense REVEL 0.82 meets the PP3 moderate threshold of >= 0.773 but not the strong threshold of >= 0.932.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history needed to judge high specificity for a single-gene disease are unavailable.
PP5	Not met	Not met: ClinVar has zero expert-panel submissions and laboratory submissions classify the exact variant as uncertain significance, not pathogenic or likely pathogenic.	clinvar PMID:25394175
BA1	Not assessed	Not assessed: gnomAD grpmax FAF is unavailable, although the observed total frequency is only 6.197046239880223e-07 versus the 0.05 BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not assessed	Not assessed: required gnomAD grpmax FAF is unavailable; observed total AF is 6.197046239880223e-07, but no disorder-specific maximum-credible-frequency calculation is supplied.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes, and no qualifying healthy-adult genotype observation is documented for BS2.	gnomad_v4
BS3	Not assessed	Not assessed: no well-established benign functional assay was identified showing that KIT V654A has no damaging effect on protein function or splicing.
BS4	Not assessed	Not assessed: no affected family members with negative variant testing are documented.
BP1	Not met	Not met: KIT disease-associated alterations are described as mainly activating gain-of-function mutations, not primarily truncating variants.	PMID:16751810 oncokb
BP2	Not assessed	Not assessed: no phase-resolved affected-proband observation shows this variant in trans or cis with a pathogenic variant under the BP2 rule.	clinvar PMID:18623623
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: missense REVEL 0.82 exceeds the BP4 supporting threshold of <= 0.29, and SpliceAI cannot substitute for a gray-zone REVEL result.	revel
BP5	Not assessed	Not assessed: no case evidence establishes an alternate molecular basis for the patient's disease alongside this variant.
BP6	Not met	Not met: no expert-panel classification or reputable benign report exists for the exact variant, while ClinVar reports 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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