KIT c.101C>T, p.Pro34Leu
NM_000222.2:c.101C>T
COSMIC ID: COSM5945004
Variant of Uncertain Significance (VUS)
Variant NM_000222.2:c.101C>T (P34L) in KIT is classified as VUS due to only Moderate PM2 (rare in controls) and Supporting BP4 (benign computational evidence) being met; no additional pathogenic or benign criteria apply.
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.101C>T
Protein Change
P34L
Location
Exon 2
(Exon 2 of 21)
5'Exon Structure (21 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 34 in gene KIT
Alternate Identifiers
COSM5945004
Variant interpretation based on transcript NM_000222.3
Genome Browser
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HGVS InputNM_000222:c.101C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00602%
Rare
Highest in Population
Remaining individuals
0.0139%
Low Frequency
Global: 0.00602%
Remaining individuals: 0.0139%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282564Alt: 17Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00602%, 17/282564 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0139%, 1/7218 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Uncertain Significance (VUS)
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
4 VUS
2 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (2 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 34 in gene KIT
Functional Summary
The KIT P34L 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
0.157
0.157
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: -0.76polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where loss of function (LoF) is a known mechanism of disease (e.g., nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single exon deletion in a LoF gene)". The evidence for this variant shows: it is a missense change (P34L), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but different nucleotide change". The evidence for this variant shows: no previously established pathogenic variant causes P34L via a different nucleotide. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: de novo status has not been assessed. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional studies are available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence in affected individuals significantly increased compared with controls". The evidence for this variant shows: no case-control data in affected individuals. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot or well-established functional domain without benign variation". The evidence for this variant shows: P34L is not in a known mutational hotspot or defined functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)". The evidence for this variant shows: it is extremely rare in population databases (MAF=0.00602% in gnomAD, no homozygotes). Therefore, this criterion is applied at Moderate strength.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders". The evidence for this variant shows: no data on allelic phase with other variants. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants". The evidence for this variant shows: P34L is a missense change without alteration in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic variant at residue 34 has been reported. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: de novo status is unknown. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: KIT has many missense variants (both benign and pathogenic), and benign missense rate is not low. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene/gene product". The evidence for this variant shows: in silico tools predict benign impact (CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI, REVEL=0.16) and SpliceAI=0.02. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no clinical phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence". The evidence for this variant shows: ClinVar reports only VUS or likely benign, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)". The evidence for this variant shows: MAF=0.00602%, well below >5%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder". The evidence for this variant shows: MAF=0.00602%, below expected maximum for KIT-associated disorders. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age". The evidence for this variant shows: observed in gnomAD but penetrance data unknown. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members". The evidence for this variant shows: no family data on segregation. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease". The evidence for this variant shows: KIT disease mechanism is gain-of-function via missense, not LoF. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant". The evidence for this variant shows: phasing with other variants is unknown. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function". The evidence for this variant shows: it is a missense substitution, not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". The evidence for this variant shows: in silico predictors (CADD, PolyPhen, MetaSVM, MetaLR, PrimateAI, REVEL=0.16) predict benign effect and SpliceAI=0.02 indicates no splicing impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no cases reported with an alternate molecular cause. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence". The evidence for this variant shows: ClinVar submissions are VUS/likely benign; no reputable source reports it as benign without evidence. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing". The evidence for this variant shows: it is a missense change, not synonymous. Therefore, this criterion is not applied.