ClinVar Miner

Submissions for variant NM_000222.3(KIT):c.2043T>G (p.Phe681Leu)

gnomAD frequency: 0.00003  dbSNP: rs878853763
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000228275 SCV000283917 uncertain significance Gastrointestinal stromal tumor 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 681 of the KIT protein (p.Phe681Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 237253). 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 disruptive. 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.
Genetic Services Laboratory, University of Chicago RCV001818566 SCV002067517 uncertain significance not specified 2020-07-24 criteria provided, single submitter clinical testing DNA sequence analysis of the KIT gene demonstrated a sequence change, c.2043T>G, in exon 14 that results in an amino acid change, p.Phe681Leu. This sequence change does not appear to have been previously described in patients with KIT-related disorders and has been described in the gnomAD database in one individual, with a low overall population frequency of 0.003% (dbSNP rs878853763). The p.Phe681Leu change affects a highly conserved amino acid residue located in a domain of the KIT protein that is known to be functional. The p.Phe681Leu substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, MutationTaster, REVEL). Due to the lack of functional studies, the clinical significance of the p.Phe681Leu change remains unknown at this time.
Ambry Genetics RCV002417985 SCV002721743 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-10 criteria provided, single submitter clinical testing The p.F681L variant (also known as c.2043T>G), located in coding exon 14 of the KIT gene, results from a T to G substitution at nucleotide position 2043. The phenylalanine at codon 681 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is conserved. 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.

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