4-54738462-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PVS1_ModerateBS2
The NM_000222.3(KIT):c.2836C>T(p.Arg946*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,042 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000222.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250900Hom.: 1 AF XY: 0.0000295 AC XY: 4AN XY: 135676
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461808Hom.: 1 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727204
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74416
ClinVar
Submissions by phenotype
KIT-related disorder Uncertain:2
BS2, PP3 -
The KIT c.2836C>T variant is predicted to result in premature protein termination (p.Arg946*). This variant was reported as a likely pathogenic variant in the heterozygous condition in two individuals with breast cancer (Supplementary Table S3, Sun et al 2017. PubMed ID: 28724667). This variant was also reported in three individuals with primary lung or colon cancer (Table 2, Ow et al. 2019. PubMed ID: 31350202). This variant is reported in 0.025% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/4-55604628-C-T) and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/576610/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
not provided Uncertain:2
Nonsense variant predicted to result in protein truncation as the last 31 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; Observed in individuals with breast, colon, and lung cancer (PMID: 28724667, 31350202); This variant is associated with the following publications: (PMID: 34426522, 28724667, 31350202) -
KIT: PVS1:Moderate -
Acute myeloid leukemia;C0024899:Mastocytosis;C0080024:Piebaldism;C0153594:Malignant tumor of testis;C0238198:Gastrointestinal stromal tumor Uncertain:1
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Gastrointestinal stromal tumor Uncertain:1
This sequence change creates a premature translational stop signal (p.Arg946*) in the KIT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 31 amino acid(s) of the KIT protein. This variant is present in population databases (rs139000082, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with breast cancer, lung cancer, and colon cancer (PMID: 28724667, 31350202). ClinVar contains an entry for this variant (Variation ID: 576610). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Acute myeloid leukemia;C0080024:Piebaldism;C0238198:Gastrointestinal stromal tumor;C1136033:Cutaneous mastocytosis;C1336708:Germ cell tumor of testis Uncertain:1
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Hereditary cancer-predisposing syndrome Benign: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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at