ClinVar Miner

Submissions for variant NM_000222.3(KIT):c.2056C>T (p.Arg686Cys)

gnomAD frequency: 0.00005  dbSNP: rs148771698
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000458048 SCV000550083 uncertain significance Gastrointestinal stromal tumor 2023-12-29 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 686 of the KIT protein (p.Arg686Cys). This variant is present in population databases (rs148771698, gnomAD 0.02%). This missense change has been observed in individual(s) with melanoma (PMID: 23020152). ClinVar contains an entry for this variant (Variation ID: 409744). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KIT function (PMID: 23020152). 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.
Ambry Genetics RCV001014252 SCV001174940 uncertain significance Hereditary cancer-predisposing syndrome 2024-07-26 criteria provided, single submitter clinical testing The p.R686C variant (also known as c.2056C>T), located in coding exon 14 of the KIT gene, results from a C to T substitution at nucleotide position 2056. The arginine at codon 686 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV003324750 SCV004031036 uncertain significance not provided 2023-05-17 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with melanoma (Bourillon et al., 2013); Published functional studies demonstrate a damaging effect: reduced activation (Bourillon et al., 2013); This variant is associated with the following publications: (PMID: 23020152)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000458048 SCV005402164 uncertain significance Gastrointestinal stromal tumor 2023-12-24 criteria provided, single submitter clinical testing The KIT c.2056C>T (p.Arg686Cys) missense change has a maximum subpopulation frequency of 0.017% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, and a functional assay showed reduction in tyrosine phosphorylation (PMID: 23020152). This variant has been reported in an individual with melanoma (PMID: 23020152). To our knowledge, this variant has not been reported in individuals with KIT-related gastrointestinal stromal tumor. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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