Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001851861 | SCV002296415 | uncertain significance | Renal cell carcinoma | 2021-09-23 | criteria provided, single submitter | clinical testing | This variant has been observed in an individual with bilateral papillary renal carcinoma, stomach cancer, and rectal cancer (PMID: 9140397). ClinVar contains an entry for this variant (Variation ID: 13885). 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. Experimental studies have shown that this variant affects MET protein function (PMID: 9826708). This variant is not present in population databases (ExAC no frequency). This sequence change replaces tyrosine with cysteine at codon 1248 of the MET protein (p.Tyr1248Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. |
| Ambry Genetics | RCV002362584 | SCV002625724 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2021-06-29 | criteria provided, single submitter | clinical testing | The p.Y1248C variant (also known as c.3743A>G), located in coding exon 18 of the MET gene, results from an A to G substitution at nucleotide position 3743. The tyrosine at codon 1248 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant is reported in an individual with bilateral papillary renal cell carcinoma and gastric cancer (Schmidt L et al. Nat Genet, 1997 May;16:68-73). Functional studies indicate that the p.Y1248C alteration increases tyrosine kinase activity and confers cell transformation properties (Jeffers M et al. Proc Natl Acad Sci U S A, 1997 Oct;94:11445-50). Based on structural analysis, this variant is located in the tyrosine kinase domain and is mildly destabilizing to the local structure (Yuan H et al. Eur J Med Chem, 2018 Jan;143:491-502; Ambry internal data). This amino acid position is well conserved in available vertebrate species.This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Myriad Genetics, |
RCV000014899 | SCV004019526 | likely pathogenic | Papillary renal cell carcinoma type 1 | 2023-03-02 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 9140397, 34882875]. Functional studies indicate this variant impacts protein function [PMID: 9326629, 9826708, 10498872]. |
| OMIM | RCV000014899 | SCV000035154 | pathogenic | Papillary renal cell carcinoma type 1 | 1997-05-01 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000441479 | SCV000505013 | likely pathogenic | Carcinoma | 2016-05-13 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000420374 | SCV000505014 | likely pathogenic | Renal carcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
| Database of Curated Mutations |
RCV000430628 | SCV000505015 | likely pathogenic | Neoplasm | 2014-12-26 | no assertion criteria provided | literature only |