Submissions for variant NM_000222.3(KIT):c.910A>G (p.Thr304Ala)

gnomAD frequency: 0.00006  dbSNP: rs202052259

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081377	SCV000560704	likely benign	Gastrointestinal stromal tumor	2024-01-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001018858	SCV001180145	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-21	criteria provided, single submitter	clinical testing	The p.T304A variant (also known as c.910A>G), located in coding exon 5 of the KIT gene, results from an A to G substitution at nucleotide position 910. The threonine at codon 304 is replaced by alanine, an amino acid with similar properties. This alteration was seen in a patient with piebaldism who was also positive for another alteration in the KIT gene, p.E583D (Lee H et al. J. Dermatol. Sci., 2014 Oct;76:74-6). This amino acid position is highly 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.
Illumina Laboratory Services, Illumina	RCV001147190	SCV001307977	uncertain significance	Piebaldism	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV001081377	SCV001308941	likely benign	Gastrointestinal stromal tumor	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV001148078	SCV001308942	benign	Mastocytosis	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Sema4, Sema4	RCV001018858	SCV002536409	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001081377	SCV002584744	uncertain significance	Gastrointestinal stromal tumor	2022-07-05	criteria provided, single submitter	clinical testing	The KIT c.910A>G (p.Thr304Ala) missense change has a maximum frequency of 0.28% 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. This variant has been reported in an individual with piebaldism who harbored a second missense variant in KIT however it was not known if the variants were on the same or opposite alleles (PMID: 25176472). To our knowledge, this variant has not been reported in individuals with 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034511	SCV000043277	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153322	SCV003843702	likely pathogenic	Ovarian cancer	2022-01-01	flagged submission	clinical testing