ClinVar Miner

Submissions for variant NM_000245.4(MET):c.3220A>G (p.Ser1074Gly)

gnomAD frequency: 0.00001  dbSNP: rs764947837
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001214128 SCV001385794 uncertain significance Renal cell carcinoma 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1092 of the MET protein (p.Ser1092Gly). This variant is present in population databases (rs764947837, gnomAD 0.002%). 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: 943852). 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 not expected to disrupt MET protein function with a negative 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.
Ambry Genetics RCV002322035 SCV002611055 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-24 criteria provided, single submitter clinical testing The p.S1092G variant (also known as c.3274A>G), located in coding exon 14 of the MET gene, results from an A to G substitution at nucleotide position 3274. The serine at codon 1092 is replaced by glycine, an amino acid with similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). This amino acid position is not 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.

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