Variant classification summary

NM_000222.2:c.148G>T

KIT · NP_000213.1:p.(Val50Leu) · NM_000222.2

GRCh37: chr4:55561758 G>T · GRCh38: chr4:54695592 G>T

Gene: KIT Transcript: NM_000222.2

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

KIT

Transcript

NM_000222.2

Protein

NP_000213.1:p.(Val50Leu)

gnomAD AF

5.390154232758012e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The KIT c.148G>T (p.Val50Leu) variant has been reported in ClinVar with predominantly uncertain significance submissions, with additional likely benign and benign submissions and no expert-panel consensus.

2

This variant is present in population databases at low frequency, measuring 0.00779% in gnomAD v2.1 and 0.00539% in gnomAD v4.1, which is below the 0.1% non-VCEP PM2 threshold and below benign stand-alone or strong frequency thresholds.

3

Computational evidence favors little or no impact, with SpliceAI predicting no significant splice effect (maximum delta score 0.01), a low REVEL score of 0.125, and a BayesDel score of -0.628781.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	Not met	This variant is a missense substitution, NP_000213.1:p.(Val50Leu), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. SpliceAI also predicts no significant splice effect (max delta score 0.01), so available evidence does not support applying PVS1.	pvs1_variant_assessment pvs1_gene_context spliceai
PS1	Not assessed	No reviewed evidence was identified showing that a different nucleotide change creates the same KIT p.(Val50Leu) amino acid substitution with an established pathogenic or likely pathogenic classification.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3	Not assessed	No well-established functional study of this exact variant was identified showing a damaging effect on KIT function.	oncokb
PS4	Not met	Available evidence does not show that this variant is significantly enriched in affected individuals compared with controls. ClinVar shows mixed clinical interpretations, and the variant is present in gnomAD at 0.00779% in v2.1 and 0.00539% in v4.1.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant has not been shown to lie in a mutational hotspot or a well-established critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at KIT codon 50.	hotspots
PM2	Met	Population frequency is below the non-VCEP PM2 threshold of 0.1%. This variant is present at 0.00779% in gnomAD v2.1 (22/282496 alleles) and 0.00539% in gnomAD v4.1 (87/1614054 alleles), with no homozygotes reported in either dataset.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This criterion is not applicable because the variant is a missense substitution and does not change protein length.
PM5	Not assessed	No reviewed same-residue pathogenic or likely pathogenic comparator was established for KIT codon 50. The retrieved PM5 candidate review did not confirm a safe basis to apply classic same-residue PM5 logic from available comparator evidence.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	Available evidence does not establish that KIT meets PP2 requirements for a gene with a low rate of benign missense variation and a common pathogenic missense mechanism at a level suitable for criterion application.
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score 0.01), REVEL is 0.125, and BayesDel is -0.628781, so in silico evidence does not support PP3.	spliceai revel bayesdel
PP4	Not assessed	No phenotype information was provided that is sufficiently specific to apply PP4.
PP5	Not assessed	ClinVar shows mixed submissions and no expert-panel classification for this variant, so a reputable-source-only pathogenic assertion was not used.	clinvar
BA1	Not met	Population frequency is below the non-VCEP BA1 threshold of 1%. The highest observed population frequency is 0.01475% in gnomAD v2.1 and 0.00937% in gnomAD v4.1, both well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency is below the non-VCEP BS1 threshold of 0.3%. The highest observed population frequency is 0.01475% in gnomAD v2.1 and 0.00937% in gnomAD v4.1, both below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults in a manner sufficient to support BS2.
BS3	Not assessed	No well-established functional study of this exact variant was identified showing normal KIT function.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	This criterion is not applicable because KIT disease mechanisms are not limited to truncating variants, so a missense change in this gene does not support BP1.
BP2	Not assessed	No phase information was identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP3	N/A	This criterion is not applicable because the variant is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	Multiple computational results favor no clinically meaningful impact. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, REVEL is low at 0.125, and BayesDel is -0.628781, which does not support a deleterious effect.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular diagnosis or alternate established cause for the relevant phenotype was identified, so BP5 was not assessed.
BP6	Not assessed	A reputable-source-only benign assertion was not used because ClinVar shows mixed submissions and no expert-panel benign or likely benign consensus.	clinvar
BP7	N/A	This criterion is not applicable because the variant is not a synonymous or deep intronic change.

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