Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000534092 | SCV000658394 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-07-25 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 397 of the RET protein (p.Val397Met). This variant is present in population databases (rs183729115, gnomAD 0.007%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22174939). ClinVar contains an entry for this variant (Variation ID: 477307). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. |
| Laboratory of Molecular Epidemiology of Birth Defects, |
RCV003153730 | SCV003843754 | likely pathogenic | Ovarian cancer | 2022-01-01 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV004024396 | SCV005028190 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-10-15 | criteria provided, single submitter | clinical testing | The p.V397M variant (also known as c.1189G>A), located in coding exon 6 of the RET gene, results from a G to A substitution at nucleotide position 1189. The valine at codon 397 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in a Chinese Hirschsprung disease patient; however, this patient was also found to carry a p.Y1062C alteration in RET that was confirmed to be in cis with the p.V397M alteration (So MT et al. PLoS One, 2011 Dec;6:e28986). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |