Submissions for variant NM_000222.3(KIT):c.1951A>T (p.Met651Leu)

gnomAD frequency: 0.00001  dbSNP: rs534209826

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458431	SCV000550103	uncertain significance	Gastrointestinal stromal tumor	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 651 of the KIT protein (p.Met651Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 409763). 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 tolerated. 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	RCV002418399	SCV002718798	benign	Hereditary cancer-predisposing syndrome	2023-02-14	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.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153628	SCV003843547	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV003319356	SCV004023707	uncertain significance	not provided	2023-02-02	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
PreventionGenetics, part of Exact Sciences	RCV004748774	SCV005364844	uncertain significance	KIT-related disorder	2024-08-14	no assertion criteria provided	clinical testing	The KIT c.1951A>T variant is predicted to result in the amino acid substitution p.Met651Leu. This variant has been reported as a variant of uncertain significance in an individual with breast cancer (Chen et al. 2020. PubMed ID: 32091409). This variant is reported in 0.10% of alleles in individuals of East Asian descent in gnomAD, which may be too common to be a primary cause of disease. This variant has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/409763/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.