Submissions for variant NM_000222.3(KIT):c.878A>G (p.Asn293Ser)

gnomAD frequency: 0.00034  dbSNP: rs137909416

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231125	SCV000283952	likely benign	Gastrointestinal stromal tumor	2025-01-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018319	SCV001179543	benign	Hereditary cancer-predisposing syndrome	2024-08-20	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Laboratory Services, Illumina	RCV001147187	SCV001307973	uncertain significance	Piebaldism	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001147188	SCV001307974	benign	Mastocytosis	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000231125	SCV001307976	uncertain significance	Gastrointestinal stromal tumor	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV001018319	SCV002536408	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000231125	SCV004015804	likely benign	Gastrointestinal stromal tumor	2023-07-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355985	SCV001551028	uncertain significance	not provided		no assertion criteria provided	clinical testing	The KIT p.Asn293Ser variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs137909416), ClinVar (classified as likely benign by Invitae for gastrointestinal stroma tumor) and in Cosmic (FATHMM predicted pathogenic; score=0.82). The variant was also identified in control databases in 49 of 282762 chromosomes at a frequency of 0.000173 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 34 of 24966 chromosomes (freq: 0.001362), Latino in 5 of 35440 chromosomes (freq: 0.000141), South Asian in 3 of 30608 chromosomes (freq: 0.000098) and European (non-Finnish) in 7 of 129090 chromosomes (freq: 0.000054), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) and Other populations. The variant occurs outside of the splicing consensus sequence however 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. The p.Asn293 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. 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.
PreventionGenetics, part of Exact Sciences	RCV003967615	SCV004776885	likely benign	KIT-related disorder	2022-04-10	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).