Submissions for variant NM_000245.4(MET):c.2318C>T (p.Pro773Leu)

gnomAD frequency: 0.00009  dbSNP: rs771333219

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001293447	SCV000553327	uncertain significance	Renal cell carcinoma	2025-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 791 of the MET protein (p.Pro791Leu). This variant is present in population databases (rs771333219, gnomAD 0.05%). This missense change has been observed in individual(s) with gastric cancer (PMID: 12920089). ClinVar contains an entry for this variant (Variation ID: 411912). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000572470	SCV000673683	benign	Hereditary cancer-predisposing syndrome	2022-11-18	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	RCV003492062	SCV000838261	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001292908	SCV001481604	uncertain significance	Osteofibrous dysplasia	2020-02-23	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001566122	SCV001789595	uncertain significance	not provided	2025-03-11	criteria provided, single submitter	clinical testing	Observed in an individual with familial gastric cancer (PMID: 12920089); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16000876, 31023376, 12920089, 35977101)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001566122	SCV002774814	uncertain significance	not provided	2024-08-31	criteria provided, single submitter	clinical testing	The MET c.2372C>T (p.Pro791Leu) variant has been reported in the published literature in a family affected with gastric cancer (PMID: 12920089 (2003)). The frequency of this variant in the general population, 0.00055 (19/34426 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001566122	SCV003800519	uncertain significance	not provided	2022-03-09	criteria provided, single submitter	clinical testing	The MET c.2372C>T; p.Pro791Leu variant (rs771333219) is reported in the literature in an individual affected with familial gastric cancer (Kim 2003). This variant is reported in ClinVar (Variation ID: 411912) and is found in the Latino population with an allele frequency of 0.06% (19/34426 alleles) in the Genome Aggregation Database. The proline at codon 791 is highly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.303). However, given the lack of clinical and functional data, the significance of the p.Pro791Leu variant is uncertain at this time. References: Kim IJ et al. A novel germline mutation in the MET extracellular domain in a Korean patient with the diffuse type of familial gastric cancer. J Med Genet. 2003 Aug;40(8):e97. PMID: 12920089.
Revvity Omics, Revvity	RCV001566122	SCV003808788	uncertain significance	not provided	2023-10-20	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470498	SCV004192500	uncertain significance	Autosomal recessive nonsyndromic hearing loss 97	2024-02-29	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001566122	SCV001809526	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001566122	SCV001971622	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004745408	SCV005349369	uncertain significance	MET-related disorder	2024-06-19	no assertion criteria provided	clinical testing	The MET c.2372C>T variant is predicted to result in the amino acid substitution p.Pro791Leu. This variant has been reported in an individual with a personal and family history of gastric cancer (Figure 1, Kim et al. 2003. PubMed ID: 12920089). Two siblings of this individual, aged 38 and 43 years, harbored this variant, but were unaffected at the time of testing (Figure 1, Kim et al. 2003. PubMed ID: 12920089). This variant is reported in 0.055% of alleles in individuals of Latino descent in gnomAD and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/411912/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.