Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000549644 | SCV000630449 | likely pathogenic | Gastrointestinal stromal tumor | 2019-01-03 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In an experimental study, this missense change lead to constitutive autophosphorylation of KIT, which was inhibited by imatinib (PMID: 17489795). This missense change has been reported in a melanoma and a gastrointestinal stromal tumor (GIST), however it is not known whether this variant was of germline or somatic origin (PMID: 21569090, 17489795). This missense change was also observed in an individual with GIST and cutaneous mastocytosis (Invitae) and segregates with GIST in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 375924). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 655 of the KIT protein (p.Asn655Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. |
| Ambry Genetics | RCV004639231 | SCV005132064 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-05-07 | criteria provided, single submitter | clinical testing | The p.N655K variant (also known as c.1965T>G), located in coding exon 13 of the KIT gene, results from a T to G substitution at nucleotide position 1965. The asparagine at codon 655 is replaced by lysine, an amino acid with similar properties. This variant was reported in multiple individuals with features consistent with KIT-related gastrointestinal stromal tumor syndrome (Fornasarig M et al. J Pers Med, 2020 Nov;10; Ingley KM et al. NPJ Genom Med, 2024 Mar;9:24; External communication). A protein functional study demonstrated this variant to result in autophosphorylation and to be sensitive to kinase inhibitors (Kinoshita K et al. Am J Gastroenterol, 2007 May;102:1134-6). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |