Submissions for variant NM_000245.4(MET):c.1291A>G (p.Met431Val)

gnomAD frequency: 0.00003  dbSNP: rs766929091

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002233270	SCV000822770	uncertain significance	Renal cell carcinoma	2023-07-12	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 572844). This variant has not been reported in the literature in individuals affected with MET-related conditions. This variant is present in population databases (rs766929091, gnomAD 0.03%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 431 of the MET protein (p.Met431Val).
Ambry Genetics	RCV001010793	SCV001171038	benign	Hereditary cancer-predisposing syndrome	2023-11-21	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.
GeneDx	RCV003226970	SCV003923786	uncertain significance	not provided	2022-11-07	criteria provided, single submitter	clinical testing	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
Neuberg Centre For Genomic Medicine, NCGM	RCV003447555	SCV004175831	uncertain significance	Arthrogryposis, distal, IIa 11	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.1291A>G (p.Met431Val) variant in MET gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Met431Va variant has allele frequency 0.003% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid change p.Met431Val in MET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 431 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance (VUS).
PreventionGenetics, part of Exact Sciences	RCV004723086	SCV005340862	uncertain significance	MET-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The MET c.1A>G variant is predicted to disrupt the translation initiation site (Start Loss). This variant is also known as c.1291A>G (p.Met431Val) under the hereditary cancer primary transcript NM_000245.4. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.026% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/572844/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.