ClinVar Miner

Submissions for variant NM_000245.4(MET):c.1125C>G (p.Asn375Lys)

dbSNP: rs776693512
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564467 SCV000673750 benign Hereditary cancer-predisposing syndrome 2024-07-02 criteria provided, single submitter clinical testing This alteration is classified as 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 RCV000709031 SCV000838246 uncertain significance Papillary renal cell carcinoma type 1 2018-07-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001293434 SCV001233164 uncertain significance Renal cell carcinoma 2025-01-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 375 of the MET protein (p.Asn375Lys). This variant is present in population databases (rs776693512, gnomAD 0.03%). This missense change has been observed in individual(s) with lung cancer (PMID: 28294470). ClinVar contains an entry for this variant (Variation ID: 485743). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MET protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects MET function (PMID: 28294470). 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.
GeneDx RCV003317290 SCV004021473 uncertain significance not provided 2023-01-19 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; Published functional studies demonstrate reduced proliferation capacity and impaired pathway activation (Tode et al., 2017); This variant is associated with the following publications: (PMID: 31342590, 28294470, 33854337)

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