ClinVar Miner

Submissions for variant NM_000222.2(KIT):c.1669T>C (p.Trp557Arg) (rs121913235)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Database of Curated Mutations (DoCM) RCV000442970 SCV000504168 pathogenic Cutaneous melanoma 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425331 SCV000504169 pathogenic Thymoma 2014-10-02 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432558 SCV000504170 likely pathogenic Gastrointestinal stroma tumor 2015-07-14 no assertion criteria provided literature only
Invitae RCV000432558 SCV000630433 likely pathogenic Gastrointestinal stroma tumor 2017-10-27 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with arginine at codon 557 of the KIT protein (p.Trp557Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with multiple gastrointestinal stromal tumors (GIST), hyperpigmentation and dysphagia in one family (PMID: 14977822), and with GIST in another family (PMID: 10680913). ClinVar contains an entry for this variant (Variation ID: 375909). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. While functional studies have not been reported for this p.Trp557Arg variant, the tryptophan residue is located in the KIT juxtamembrane domain, which is required for KIT autoinhibition (PMID: 16226710, 12697809).  A different substitution at this codon, p.Trp557Ala, was shown to result in loss of phosphorylation inhibition and gain-of-function of the KIT protein (PMID: 10224103). 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.

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