Submissions for variant NM_000222.3(KIT):c.200C>G (p.Thr67Ser)

gnomAD frequency: 0.00045  dbSNP: rs144933028

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234428	SCV000283916	likely benign	Gastrointestinal stromal tumor	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000332028	SCV000449871	uncertain significance	Piebaldism	2018-01-13	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	RCV000234428	SCV000449872	uncertain significance	Gastrointestinal stromal tumor	2018-01-13	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	RCV000282556	SCV000449873	likely benign	Mastocytosis	2018-01-13	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.
Genetic Services Laboratory, University of Chicago	RCV000503289	SCV000595432	uncertain significance	not specified	2016-11-21	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764541	SCV000895627	uncertain significance	Gastrointestinal stromal tumor; Mastocytosis; Piebaldism; Malignant tumor of testis; Acute myeloid leukemia	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001014023	SCV001174680	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-21	criteria provided, single submitter	clinical testing	The p.T67S variant (also known as c.200C>G), located in coding exon 2 of the KIT gene, results from a C to G substitution at nucleotide position 200. The threonine at codon 67 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001753684	SCV002007156	uncertain significance	not provided	2023-07-11	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
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001753684	SCV002010058	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000234428	SCV003843011	uncertain significance	Gastrointestinal stromal tumor	2023-01-24	criteria provided, single submitter	clinical testing	The KIT c.200C>G (p.Thr67Ser) missense change has a maximum subpopulation frequency of 0.065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. 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	RCV001753684	SCV004150651	benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	KIT: BS1, BS2
GenomeConnect - Invitae Patient Insights Network	RCV001535624	SCV001749650	not provided	Gastrointestinal stromal tumor; Piebaldism		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 09-15-2017 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV003919917	SCV004736477	likely benign	KIT-related disorder	2022-03-22	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).