About KIT
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KIT c.148G>T, p.(Val50Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
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.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
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.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting; combination = 1 moderate + 1 supporting benign, which maps to VUS because the evidence is conflicting.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
87 / 1,614,054 alleles
gnomAD v4.1: 87 / 1,614,054 alleles. Recorded AF 5.39015e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.78772e-05; MAF= 0.00779%, 22/282496 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000147454; MAF= 0.01475%, 19/128854 alleles, homozygotes = 0); grpmax FAF= 0.00049825.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
11 reported laboratory submissions
9 Uncertain significance · 1 Likely benign · 1 Benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KIT, a receptor tyrosine kinase, is recurrently mutated in gastrointestinal stromal tumors.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV105160851, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 16 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
No criteria match.
Met · 2
PM2 ModeratePopulation 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. Details ▾Hide ▴
Rule
Non-VCEP default population cutoff: PM2 if AF < 0.1%
Evidence considered
- gnomAD v2.1 AF 7.78772e-05
- 22/282496
- homozygotes 0
- gnomAD v4.1 AF 5.39015e-05
- 87/1614054
Sources
BP4 SupportingMultiple 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. Details ▾Hide ▴
Rule
Generic ACMG computational benign-supporting assessment using available predictors
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.125
- BayesDel -0.628781
Sources
Not met · 6 · evaluated, threshold not reached
PVS1 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. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 fallback not applicable to this missense variant
Evidence considered
- Missense variant outside default generic PVS1 null-variant buckets
- SpliceAI max delta score 0.01
Sources
PS4 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. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 409722 with mixed submissions
- gnomAD v2.1 AF 7.78772e-05
- gnomAD v4.1 AF 5.39015e-05
Still missing
- No case-control or prevalence study for this exact variant was identified.
Sources
PM1 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. Details ▾Hide ▴
Evidence considered
- No hotspot row found for KIT V50
- Variant does not lie in a statistically significant hotspot
Sources
PP3 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. Details ▾Hide ▴
Rule
No gene-specific computational rule available; multiple in silico predictors reviewed under generic ACMG context
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.125
- BayesDel -0.628781
Sources
BA1 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%. Details ▾Hide ▴
Rule
Non-VCEP default population cutoff: BA1 if AF > 1%
Evidence considered
- gnomAD v2.1 highest subpopulation AF 0.000147454
- gnomAD v4.1 highest subpopulation AF 9.37295e-05
Sources
BS1 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%. Details ▾Hide ▴
Rule
Non-VCEP default population cutoff: BS1 if AF > 0.3%
Evidence considered
- gnomAD v2.1 highest subpopulation AF 0.000147454
- gnomAD v4.1 highest subpopulation AF 9.37295e-05
Sources
Not assessed · 16 · no assessment recorded
PS1 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. Details ▾Hide ▴
Still missing
- Direct same-amino-acid comparator review was not available in the retrieved sources.
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Still missing
- No trio-based or parentage-confirmed de novo report was identified.
PS3 No well-established functional study of this exact variant was identified showing a damaging effect on KIT function. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No variant-specific functional assay was identified.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
- No phase data or recessive case observations were identified.
PM5 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. Details ▾Hide ▴
Evidence considered
- PM5 candidate review found no comparator variants and did not support automatic PM5 use
Still missing
- No confirmed pathogenic or likely pathogenic same-residue comparator was identified.
Sources
pm5_candidates
PM6 No assumed de novo occurrence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Still missing
- No probable de novo report was identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family segregation report or meiosis count was identified.
PP2 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. Details ▾Hide ▴
Still missing
- No gene-level missense constraint framework for PP2 was provided.
PP4 No phenotype information was provided that is sufficiently specific to apply PP4. Details ▾Hide ▴
Still missing
- Clinical phenotype and testing context were not available for phenotype-specific assessment.
PP5 ClinVar shows mixed submissions and no expert-panel classification for this variant, so a reputable-source-only pathogenic assertion was not used. Details ▾Hide ▴
BS2 No evidence was identified showing this variant in healthy adults in a manner sufficient to support BS2. Details ▾Hide ▴
Still missing
- No adult phenotyped carrier data were identified.
BS3 No well-established functional study of this exact variant was identified showing normal KIT function. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No benign functional assay result was identified for this variant.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family-level discordance data were identified.
BP2 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. Details ▾Hide ▴
Still missing
- No phasing data or second-variant context were identified.
BP5 No alternate molecular diagnosis or alternate established cause for the relevant phenotype was identified, so BP5 was not assessed. Details ▾Hide ▴
Still missing
- Clinical diagnosis context was not available.
BP6 A reputable-source-only benign assertion was not used because ClinVar shows mixed submissions and no expert-panel benign or likely benign consensus. Details ▾Hide ▴
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/AThis criterion is not applicable because the variant is a missense substitution and does not change protein length. Details ▾Hide ▴
Evidence considered
- Protein consequence NP_000213.1:p.(Val50Leu)
BP1 N/AThis 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. Details ▾Hide ▴
Evidence considered
- Variant is missense in KIT
BP3 N/AThis criterion is not applicable because the variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Evidence considered
- Variant type is missense substitution
BP7 N/AThis criterion is not applicable because the variant is not a synonymous or deep intronic change. Details ▾Hide ▴
Evidence considered
- Variant type is missense substitution
Identifiers
- Gene
- KIT
- Transcript
- NM_000222.2
- Coding (HGVS c.)
- NM_000222.2:c.148G>T
- Protein (HGVS p.)
- NP_000213.1:p.(Val50Leu)
- GRCh38
- chr4:54695592 G>T
- GRCh37
- chr4:55561758 G>T
- ClinVar
- 409722
- COSMIC
- COSV105160851
Gene diagram
Every interpreted variant in KIT, mapped onto the exon structure of NM_000222.2. Select a row to find it on the plot.
KITNM_000222.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in KIT
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
87 / 1,614,054 alleles
AF 5.39e-05 · 0 homozygotes · FAF 5.46e-05
gnomAD v2.1
22 / 282,496 alleles
AF 7.79e-05 · 0 homozygotes · FAF 0.000498
By genetic ancestry
gnomAD v4.1
AF 5.4e-05 · 87 / 1,614,054 alleles · 0 hom · FAF 5.5e-05
| European (Finnish)6 / 64,014 | 9.4e-05 |
| European (non-Finnish)79 / 1,180,042 | 6.7e-05 |
| Remaining individuals1 / 62,488 | 1.6e-05 |
| African/African American1 / 74,936 | 1.3e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 7.8e-05 · 22 / 282,496 alleles · 0 hom · FAF 0.0005
| European (non-Finnish)19 / 128,854 | 0.00015 |
| Remaining individuals1 / 7,210 | 0.00014 |
| European (Finnish)2 / 25,122 | 8e-05 |
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.39015e-05; MAF= 0.00539%, 87/1614054 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 9.37295e-05; MAF= 0.00937%, 6/64014 alleles, homozygotes = 0); grpmax FAF= 5.463e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.78772e-05; MAF= 0.00779%, 22/282496 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000147454; MAF= 0.01475%, 19/128854 alleles, homozygotes = 0); grpmax FAF= 0.00049825.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.125
- BayesDel
- -0.629
How the predictions were used
BP4 SupportingMultiple 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. Details ▾Hide ▴
Rule
Generic ACMG computational benign-supporting assessment using available predictors
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.125
- BayesDel -0.628781
Sources
PP3 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. Details ▾Hide ▴
Rule
No gene-specific computational rule available; multiple in silico predictors reviewed under generic ACMG context
Evidence considered
- SpliceAI max delta score 0.01
- REVEL 0.125
- BayesDel -0.628781
Sources
BP7 N/AThis criterion is not applicable because the variant is not a synonymous or deep intronic change. Details ▾Hide ▴
Evidence considered
- Variant type is missense substitution
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.125. BayesDel score = -0.628781.
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 22138009 ↗NCCN Task Force report: Evaluating the clinical utility of tumor markers in oncology.Febbo PG et al. · 2011No paper-specific finding is recorded.
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PMID 23852704 ↗Tumor markers in colorectal cancer, gastric cancer and gastrointestinal stromal cancers: European group on tumor markers 2014 guidelines update.Duffy MJ et al. · 2014No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 20963938 ↗CEBPA-Associated Familial Acute Myeloid Leukemia (AML).Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23970018 ↗Acute myeloblastic leukaemias in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 32171751 ↗Acute myeloid leukaemia in adult patients: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.No paper-specific finding is recorded.
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PMID 33226740 ↗PMID:33226740No paper-specific finding is recorded.
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PMID 22685257 ↗The UK NEQAS for Molecular Genetics scheme for gastrointestinal stromal tumour: findings and recommendations following four rounds of circulation.Wong NA et al. · 2012No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
87 / 1,614,054 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
9 Uncertain significance · 1 Likely benign · 1 Benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/409722/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55561758-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-54695592-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000222.2%3Ac.148G…
- OncoKB ↗www.oncokb.org/gene/KIT/V50L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=176257386
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.39015e-05; MAF= 0.00539%, 87/1614054 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 9.37295e-05; MAF= 0.00937%, 6/64014 alleles, homozygotes = 0); grpmax FAF= 5.463e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.78772e-05; MAF= 0.00779%, 22/282496 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000147454; MAF= 0.01475%, 19/128854 alleles, homozygotes = 0); grpmax FAF= 0.00049825.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 409722)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.125. BayesDel score = -0.628781.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KIT, a receptor tyrosine kinase, is recurrently mutated in gastrointestinal stromal tumors.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105160851, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.