Submissions for variant NM_000245.4(MET):c.1076G>A (p.Arg359Gln)

gnomAD frequency: 0.00022  dbSNP: rs201274041

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079480	SCV000111360	uncertain significance	not provided	2013-10-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001312208	SCV000166411	uncertain significance	Renal cell carcinoma	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 359 of the MET protein (p.Arg359Gln). This variant is present in population databases (rs201274041, gnomAD 0.04%). 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: 93564). 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.
Illumina Laboratory Services, Illumina	RCV000123109	SCV000466435	likely benign	Papillary renal cell carcinoma type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Ambry Genetics	RCV000567262	SCV000673699	likely benign	Hereditary cancer-predisposing syndrome	2020-05-06	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	RCV004700392	SCV000838245	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
GeneDx	RCV000079480	SCV001768625	uncertain significance	not provided	2024-08-27	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Published functional studies suggest this variant may increase MET expression but does not appear to impact cell migration or invasion (PMID: 34389035); Observed in individuals with thyroid cancer and breast cancer (PMID: 30086788, 34389035, 35264596); This variant is associated with the following publications: (PMID: 26718692, 28192086, 29049316, Rastegar2021[abstract], 34389035, 23334666, 26700204, 28873162, 28619094, 30086788, 35264596)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000079480	SCV002011114	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267846	SCV002550779	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing