Submissions for variant NM_000222.3(KIT):c.1781C>T (p.Thr594Ile)

gnomAD frequency: 0.00001  dbSNP: rs375351432

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475124	SCV000550134	uncertain significance	Gastrointestinal stromal tumor	2024-01-17	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 594 of the KIT protein (p.Thr594Ile). This variant is present in population databases (rs375351432, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with KIT-related conditions. ClinVar contains an entry for this variant (Variation ID: 409793). 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. 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	RCV001013131	SCV001173675	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The p.T594I variant (also known as c.1781C>T), located in coding exon 12 of the KIT gene, results from a C to T substitution at nucleotide position 1781. The threonine at codon 594 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237870	SCV002010059	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV003237870	SCV004025665	uncertain significance	not provided	2023-09-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27027238, 32441621)
Baylor Genetics	RCV000475124	SCV004198085	uncertain significance	Gastrointestinal stromal tumor	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003409632	SCV004107229	uncertain significance	KIT-related disorder	2024-03-12	no assertion criteria provided	clinical testing	The KIT c.1781C>T variant is predicted to result in the amino acid substitution p.Thr594Ile. To our knowledge, this variant has not been reported in the literature. This variant is reported in 3 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/). This variant is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409793/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.