Submissions for variant NM_000222.3(KIT):c.2867G>A (p.Arg956Gln)

gnomAD frequency: 0.00008  dbSNP: rs139694927

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473422	SCV000550128	uncertain significance	Gastrointestinal stromal tumor	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 956 of the KIT protein (p.Arg956Gln). This variant is present in population databases (rs139694927, gnomAD 0.02%). 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: 409787). 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	RCV001016731	SCV001177721	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-31	criteria provided, single submitter	clinical testing	The c.2867G>A (p.R956Q) alteration is located in exon 21 (coding exon 21) of the KIT gene. This alteration results from a G to A substitution at nucleotide position 2867, causing the arginine (R) at amino acid position 956 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV001753894	SCV002005534	uncertain significance	not provided	2023-08-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 32608199)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001753894	SCV002009398	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000473422	SCV004171412	uncertain significance	Gastrointestinal stromal tumor	2023-11-13	criteria provided, single submitter	clinical testing	The KIT c.2867G>A (p.Arg956Gln) missense change has a maximum subpopulation frequency of 0.015% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. 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.
CeGaT Center for Human Genetics Tuebingen	RCV001753894	SCV005051432	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003899925	SCV004712280	likely benign	KIT-related disorder	2023-11-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).