Submissions for variant NM_000245.4(MET):c.638C>T (p.Ser213Leu)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002369141	SCV002659114	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing	The p.S213L variant (also known as c.638C>T), located in coding exon 1 of the MET gene, results from a C to T substitution at nucleotide position 638. The serine at codon 213 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003594230	SCV004301519	uncertain significance	Renal cell carcinoma	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 213 of the MET protein (p.Ser213Leu). This variant is present in population databases (rs367722737, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with MET-related conditions. ClinVar contains an entry for this variant (Variation ID: 1753220). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MET protein function with a positive predictive value of 80%. 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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV004565317	SCV005049544	uncertain significance	Lymphedema	2024-03-08	criteria provided, single submitter	clinical testing	A MET c.638C>T (p.Ser213Leu) variant was identified at an allelic fraction consistent with somatic origin. This variant, to our knowledge, has not been reported in the literature in individuals with MET-related conditions. This variant has been reported in the ClinVar database by two submitters as a variant of uncertain significance in a germline state (ClinVar Variation ID: 1753220). This variant is observed on 7/1,461,786 alleles in the general population (gnomAD v4.0.0). Computational predictors are uncertain as to the impact of this variant on MET function. Due to limited information, and based on an internally developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868) and gene-specific practices from the ClinGen Criteria Specification Registry, the clinical significance of the MET c.638C>T (p.Ser213Leu) variant is uncertain at this time.