ClinVar Miner

Submissions for variant NM_000245.4(MET):c.2209A>G (p.Ser737Gly)

dbSNP: rs755571526
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001014789 SCV001175545 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing The p.S737G variant (also known as c.2209A>G), located in coding exon 8 of the MET gene, results from an A to G substitution at nucleotide position 2209. The serine at codon 737 is replaced by glycine, an amino acid with similar properties. 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001240417 SCV001413355 uncertain significance Renal cell carcinoma 2023-05-08 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 820892). This missense change has been observed in individual(s) with urothelial cancer (PMID: 33588785). This variant is present in population databases (rs755571526, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 737 of the MET protein (p.Ser737Gly). 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. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844258 SCV002103587 uncertain significance not specified 2022-02-24 criteria provided, single submitter clinical testing Variant summary: MET c.2209A>G (p.Ser737Gly) results in a non-conservative amino acid change located in the 2nd IPT (Ig-like, plexins, transcription factors) domain (IPR002909) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249220 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2209A>G, has been reported in the literature as a germline variant in an individual affected with bladder carcinoma. This report however does not provide unequivocal conclusions about association of the variant with Papillary Renal Cell Carcinoma. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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