Submissions for variant NM_000245.4(MET):c.40C>T (p.Leu14Phe)

gnomAD frequency: 0.00015  dbSNP: rs763344951

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001293449	SCV000218614	uncertain significance	Renal cell carcinoma	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 14 of the MET protein (p.Leu14Phe). This variant is present in population databases (rs763344951, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 188112). 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%. 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	RCV000561286	SCV000673698	likely benign	Hereditary cancer-predisposing syndrome	2023-08-17	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	RCV004700517	SCV000838225	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	RCV001564694	SCV001787894	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a pheochromocytoma or paraganglioma (PMID: 37529773); This variant is associated with the following publications: (PMID: 29641532, 37529773, 35264596)
Baylor Genetics	RCV003468821	SCV004192521	uncertain significance	Autosomal recessive nonsyndromic hearing loss 97	2024-01-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001564694	SCV005622928	uncertain significance	not provided	2024-10-04	criteria provided, single submitter	clinical testing	The MET c.40C>T (p.Leu14Phe) variant has been reported in the published literature in individuals with breast cancer (PMID: 35264596 (2022)) and pheochromocytoma and paraganglioma (PPGL) (PMID: 37529773 (2023)). This variant has also been observed in a reportedly healthy individual (PMID: 29641532 (2018)). The frequency of this variant in the general population, 0.00023 (8/35300 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
PreventionGenetics, part of Exact Sciences	RCV004745246	SCV005352879	uncertain significance	MET-related disorder	2024-07-18	no assertion criteria provided	clinical testing	The MET c.40C>T variant is predicted to result in the amino acid substitution p.Leu14Phe. This variant has been reported in an individual with breast cancer and in a control cohort for a large cancer study (Guindalini et al. 2022. PubMed ID: 35264596; Supplement 3 in Pritchard et al. 2018. PubMed ID: 29641532). This variant was also identified in an individual with abdominal paraganglioma and was classified as uncertain significance (Lima JV Jr et al. 2023. PubMed ID: 37529773). This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD and has been classified as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/188112). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.