Variant classification summary

NM_000222.3:c.1669_1674del

KIT · NP_000213.1:p.(Trp557_Lys558del) · NM_000222.3

GRCh37: chr4:55593600 CAGTGGA>C · GRCh38: chr4:54727434 CAGTGGA>C

Gene: KIT Transcript: NM_000222.3

Final call

Likely Pathogenic

PS3 strong PM4 moderate PM2 supporting

Variant details

Gene

KIT

Transcript

NM_000222.3

Protein

NP_000213.1:p.(Trp557_Lys558del)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS3 strong, with exact-variant Ba/F3 and xenograft assays demonstrating abnormal KIT-dependent behavior and tumor regression.

2

Likely Pathogenic: PM4 moderate, with a two-residue in-frame deletion in KIT exon 11's non-repeat juxtamembrane region.

3

Likely Pathogenic: PM2 supporting, with the exact variant absent from gnomAD v2.1 and v4.1.

Final determination: Under the generic ACMG/AMP 2015 fallback, one strong plus one moderate plus one supporting pathogenic criterion supports Likely Pathogenic, provided no benign rule is also satisfied.

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 an in-frame indel.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: confirmed maternity and paternity, a disease-affected proband, and absence of family history are not documented.	PMID:15930355 PMID:16954519
PS3	Met	Met, strong: exact-variant Ba/F3 and xenograft assays demonstrated KIT-dependent abnormal growth, drug response, apoptosis, and tumor regression.	PMID:17699867 PMID:25239608 PMID:15930355
PS4	Not met	Not met: affected-patient reports lack unaffected or population-control counts, so no case-control OR/RR or confidence interval can establish the PS4 threshold.	PMID:15930355 PMID:16954519 PMID:25394175
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, satisfying the <=0.0001 PM2 frequency threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected-proband germline observation, pathogenic variant in trans, or parent/offspring phase testing is documented.	PMID:15930355 PMID:16954519 PMID:17699867 PMID:25239608
PM4	Met	Met: the exact six-base deletion removes two amino acids in-frame from KIT exon 11, a non-repeat functional region, satisfying the PM4 definition.	PMID:15930355 PMID:17699867 PMID:25239608
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no patient-level disease presentation or assumed de novo occurrence without parental confirmation is documented.	PMID:15930355 PMID:16954519
PP1	Not assessed	Not assessed: no affected relatives, familial genotypes, phenotype concordance, or informative meioses are documented.	PMID:15930355 PMID:16954519
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the in-frame p.(Trp557_Lys558del) deletion is a protein-length-changing variant outside PP3 scope.
PP4	Not assessed	Not assessed: the patient's phenotype and family history are unavailable, preventing evaluation of phenotype specificity for a single genetic etiology.
PP5	Not met	Not met: ClinVar's exact-variant Likely pathogenic assertion is a single-submitter laboratory record, not an expert-panel reputable-source report eligible for PP5.	clinvar PMID:25394175
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no grpmax FAF approaching the >=0.05 BA1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, providing no grpmax FAF at or above the generic >=0.01 BS1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not assessed	Not assessed: no phenotyped healthy adult carrier is reported, and the required early-age full-penetrance context is undocumented.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no well-established benign functional or splicing assay demonstrates normal KIT function for the exact variant.	PMID:17699867 PMID:25239608 PMID:15930355
BS4	Not assessed	Not assessed: no tested affected relatives lacking the variant are documented, so familial non-segregation cannot be evaluated.
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is an in-frame indel.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no pathogenic variant in trans or cis, fully penetrant dominant context, or phasing result is documented.	PMID:15930355 PMID:16954519 PMID:17699867 PMID:25239608
BP3	Not met	Not met: the two-residue in-frame deletion lies in KIT's functional exon 11 juxtamembrane region, not a repetitive region without known function.	PMID:15930355 PMID:17699867 PMID:25239608
BP4	N/A	Not applicable: the in-frame p.(Trp557_Lys558del) deletion is a protein-length-changing variant outside BP4 scope.
BP5	Not assessed	Not assessed: no case documents a confirmed alternate molecular basis for disease alongside this KIT variant.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely benign classification is present; available records are non-expert and not benign.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is an in-frame indel.	generic_acmg_combination_rules

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