Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000221989 | SCV000277639 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-05-03 | criteria provided, single submitter | clinical testing | The p.V1238I pathogenic mutation (also known as c.3712G>A), located in coding exon 18 of the MET gene, results from a G to A substitution at nucleotide position 3712. The valine at codon 1238 is replaced by isoleucine, an amino acid with highly similar properties. This alteration has been reported in a French patient with papillary renal carcinoma and no known family history of kidney cancer (Schmidt L et al, Oncogene 1999 Apr; 18(14):2343-50). It has also been shown to segregate with disease in a large Spanish family with a clinical history consistent with hereditary papillary renal cell carcinoma (HPRCC) with a likelihood ratio of 348:1 (Schmidt L et al, Nat. Genet. 1997 May; 16(1):68-73; Prat E et al. Cancer Genet Cytogenet, 2006 Jan;164:142-7, Ambry internal calculations). One study examined the functional significance of this alteration by transfecting cells with MET mutant cDNA and found that while cells transfected with V1238I were phenotypically normal, they had moderately enhanced kinase activity toward an exogenous substrate when compared with wild-type MET. Further, cells expressing MET V1238I were shown to be tumorigenic in nude mice (Jeffers M et al, Proc. Natl. Acad. Sci. U.S.A. 1997 Oct; 94(21):11445-50). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Labcorp Genetics |
RCV001376555 | SCV001227878 | likely pathogenic | Renal cell carcinoma | 2023-07-18 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MET function (PMID: 9326629, 19459657). 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 expected to disrupt MET protein function. ClinVar contains an entry for this variant (Variation ID: 13883). This variant is also known as V1220I. This missense change has been observed in individual(s) with renal cell carcinoma (PMID: 9140397, 32770124, 34882875). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1238 of the MET protein (p.Val1238Ile). |
OMIM | RCV000014897 | SCV000035152 | pathogenic | Papillary renal cell carcinoma type 1 | 1997-05-01 | no assertion criteria provided | literature only | |
Genome Diagnostics Laboratory, |
RCV001579843 | SCV001808688 | pathogenic | not provided | no assertion criteria provided | clinical testing | ||
Genome Diagnostics Laboratory, |
RCV001579843 | SCV001927477 | pathogenic | not provided | no assertion criteria provided | clinical testing |