Variant classification summary

NM_000222.3:c.1679T>A

KIT · NP_000213.1:p.(Val560Asp) · NM_000222.3

GRCh37: chr4:55593613 T>A · GRCh38: chr4:54727447 T>A

Gene: KIT Transcript: NM_000222.3

Final call

Likely Pathogenic

PS1 strong PS3 supporting PM2 supporting PP3 moderate

Variant details

Gene

KIT

Transcript

NM_000222.3

Protein

NP_000213.1:p.(Val560Asp)

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: PS1 strong because the exact KIT p.Val560Asp substitution was previously reported in multiple GIST studies.

2

Likely Pathogenic: PS3 supporting because variant-specific assays showed altered KIT signaling and inhibitor response.

3

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

4

Likely Pathogenic: PP3 moderate because REVEL 0.823 meets the supplied missense threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback rules, one Strong pathogenic criterion plus one Moderate pathogenic criterion supports Likely Pathogenic; PS1 strong plus PP3 moderate meets this rule, with PS3 and PM2 additionally 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	Met	Met, because the exact KIT p.Val560Asp substitution was previously reported in multiple GIST studies, including primary tumor cases and variant-specific functional assays.	PMID:16551858 PMID:16954519 PMID:18955458 PMID:23840364 clinvar
PS2	Not assessed	Not assessed: no documented proband phenotype with confirmed maternity and paternity for KIT c.1679T>A.
PS3	Met	Met, supporting: variant-specific assays showed phosphorylated KIT and imatinib sensitivity below 100 nmol/L, consistent with altered KIT signaling but incompletely documented validation controls.	PMID:16954519 PMID:18955458 PMID:23840364 PMID:15897563
PS4	Not assessed	Not assessed: no verified exact-variant case and control counts or OR/RR with 95% CI are available for comparison against the PS4 threshold >5.0 with CI excluding 1.0.	PMID:16551858 PMID:16954519 PMID:18955458 PMID:23840364 PMID:15897563
PM1	Not assessed	Not assessed: Val560 is a documented KIT juxtamembrane hotspot, but the required absence of benign variation across the relevant region is not established.	hotspots PMID:10224103 PMID:15897563 gnomad_v2 gnomad_v4
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed allele frequency 0 versus the <=0.0001 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: PM3 is restricted to recessive disorders, and this KIT case provides no recessive-disease context or trans-phase testing.
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: V560A has functional evidence but no documented pathogenic determination, so no different pathogenic missense comparator at Val560 is established.	PMID:10224103 PMID:16551858 PMID:15897563
PM6	Not assessed	Not assessed: no proband-level assumed de novo observation for KIT c.1679T>A is documented.
PP1	Not assessed	Not assessed: no multiple affected relatives carrying KIT c.1679T>A are documented; the familial report involved a different KIT variant.	PMID:15897563
PP2	Not assessed	Not assessed: KIT missense gain-of-function is documented, but no gene-level low benign-missense rate or applicable threshold is provided.	PMID:10485475 PMID:15897563 gnomad_v2 gnomad_v4
PP3	Met	Met at moderate strength: missense REVEL 0.823 meets the generic PP3 moderate threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: the supplied evidence lacks the patient's phenotype or family history needed to establish a highly specific single-etiology disease presentation.
PP5	Not met	Not met: ClinVar shows one non-expert single-submitter Likely pathogenic assertion, with 0 expert-panel submissions, so PP5 is not triggered.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having a filtering allele frequency or grpmax FAF of at least 5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no observed allele frequency, far below the generic 1% BS1 default threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: population absence does not establish the healthy-adult carrier or homozygote observation required for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no reviewed assay demonstrates that KIT p.Val560Asp has no damaging effect on protein function or splicing.	PMID:16954519 PMID:18955458 PMID:23840364 PMID:15897563
BS4	Not assessed	Not assessed: no affected relatives tested for KIT c.1679T>A are documented, so non-segregation cannot be determined.	PMID:15897563
BP1	Not met	Not met: KIT GIST is repeatedly associated with activating missense mutations, including recurrent juxtamembrane variants, rather than primarily truncating variants.	PMID:10485475 PMID:15897563 oncokb
BP2	Not assessed	Not assessed: tumor studies report V560D with secondary KIT variants, but no germline phase or pathogenic-partner evidence establishes BP2.	PMID:16551858 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: missense REVEL 0.823 exceeds the generic BP4 supporting threshold of <=0.29.	revel
BP5	Not met	Not met: V560D is reported in GIST tumor contexts with additional KIT mutations, but no qualifying alternate molecular basis explaining disease instead of this variant is documented.	PMID:16551858 PMID:16954519 PMID:18955458 PMID:23840364
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification and instead records one non-expert Likely pathogenic assertion.	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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