Submissions for variant NM_000222.3(KIT):c.757-9A>G

gnomAD frequency: 0.00002  dbSNP: rs367986084

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554033	SCV000630521	uncertain significance	Gastrointestinal stromal tumor	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the KIT gene. It does not directly change the encoded amino acid sequence of the KIT protein. This variant is present in population databases (rs367986084, gnomAD 0.005%). 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: 458969). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
GeneDx	RCV001356232	SCV002549567	uncertain significance	not provided	2024-06-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356232	SCV001551346	uncertain significance	not provided		no assertion criteria provided	clinical testing	The KIT c.757-9A>G variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs367986084) and ClinVar (classified as a VUS by Invitae for gastrointestinal stomal tumor). The variant was identified in control databases in 6 of 281172 chromosomes at a frequency of 0.00002134 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7154 chromosomes (freq: 0.00014) and European (non-Finnish) in 5 of 128344 chromosomes (freq: 0.000039), but was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish) or South Asian populations. The c.575-9A>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However this splicing prediction has not been confirmed by RNA analysis. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.