KIT c.1351T>C, p.Ser451Pro
NM_000222.2:c.1351T>C
Variant of Uncertain Significance (VUS)
Using classification after pre-processing (Variant of Uncertain Significance (VUS)) due to LLM failure: LLM response was not valid JSON even after cleaning: Expecting ',' delimiter: line 1 column 6430 (char 6429). Raw response snippet: {"final_classification":"VUS","criteria_evaluation":[{"criterion":"PVS1","is_applied":false,"strength":"Not Applied","justification":"According to standard ACMG guidelines, the rule for PVS1 is: \"Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion) in a gene where loss of function is a known mechanism of disease.\" The evidence for this variant shows: NM_000222.2:c.1351T>C is a missense change (S451P), not a null variant. Therefore, this criterion is not applied."},{"criterion":"PS1","is_applied":false,"strength":"Not Applied","justification":"According to standard ACMG guidelines, the rule for PS1 is: \"Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.\" The evidence for this variant shows: there is no reported pathogenic variant at amino acid position 451 in KIT. Therefore, this criterion is not applied."},{"criterion":"PS2","is_applied":false,"strength":"Not Applied","justifi...
ACMG/AMP Criteria Applied
PM2
BP4
Genetic Information
Gene & Transcript Details
Gene
KIT
Transcript
NM_000222.3
MANE Select
Total Exons
21
Strand
Forward (+)
Reference Sequence
NC_000004.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000222.2 | RefSeq Select | 21 exons | Forward |
| NM_000222.1 | Alternative | 22 exons | Forward |
Variant Details
HGVS Notation
NM_000222.2:c.1351T>C
Protein Change
S451P
Location
Exon 9
(Exon 9 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Missense Variant
Related Variants
No evidence of other pathogenic variants at position 451 in gene KIT
Variant interpretation based on transcript NM_000222.3
Genome Browser
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HGVS InputNM_000222:c.1351T>C
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00213%
Rare
Highest in Population
European (non-Finnish)
0.00466%
Rare
Global: 0.00213%
European (non-Finnish): 0.00466%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282072Alt: 6Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00213%, 6/282072 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00466%, 6/128622 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 451 in gene KIT
Functional Summary
The KIT S451P variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.035
0.035
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.71polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PM2
PM2 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)
BP4
BP4 (Unknown (Pre-LLM)) Strength Modified
From pre-LLM assessment (LLM Failed)