ClinVar Miner

Submissions for variant NM_000245.4(MET):c.3352A>G (p.Ile1118Val)

dbSNP: rs755234697
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001293430 SCV000623434 uncertain significance Renal cell carcinoma 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1136 of the MET protein (p.Ile1136Val). This variant is present in population databases (rs755234697, 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: 454239). 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 RCV000570458 SCV000673717 likely benign Hereditary cancer-predisposing syndrome 2024-08-28 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Mendelics RCV000526482 SCV000838272 uncertain significance Papillary renal cell carcinoma type 1 2018-07-02 criteria provided, single submitter clinical testing
GeneDx RCV001775839 SCV002012556 uncertain significance not provided 2023-03-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 33237286)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000526482 SCV002584769 uncertain significance Papillary renal cell carcinoma type 1 2022-07-27 criteria provided, single submitter clinical testing The MET c.3406A>G (p.Ile1136Val) missense change has a maximum frequency of 0.0016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with hereditary papillary renal cell carcinoma. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics RCV003470699 SCV004192552 uncertain significance Autosomal recessive nonsyndromic hearing loss 97 2023-07-23 criteria provided, single submitter clinical testing

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