Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000198421 | SCV000255054 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2022-06-13 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1061 of the RET protein (p.Leu1061Pro). This variant is present in population databases (rs536486113, gnomAD 0.003%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 10484767). ClinVar contains an entry for this variant (Variation ID: 216725). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 10465268, 10484767, 11313948, 11390647). 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 for Molecular Medicine, |
RCV000454885 | SCV000540180 | uncertain significance | not specified | 2016-12-16 | criteria provided, single submitter | clinical testing | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in a consanguinous family in the homozygous state in siblings and heterozygous state in a cousin with Hirschprung's disease. It has not been seen in individuals with MEN2A. It was found to partially inhibit the Shc-RET interaction by in vitro studies, which affects the ability of RET to transmit downstream signals. This variant is classified in ClinVar with 1 star as VUS by Invitae. The variant has a Max MAF of 0.009% in ExAC (1 allele) and 0.003% in gnomAD (1 allele). |
| Ambry Genetics | RCV000569228 | SCV000674816 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-11-12 | criteria provided, single submitter | clinical testing | The p.L1061P variant (also known as c.3182T>C), located in coding exon 19 of the RET gene, results from a T to C substitution at nucleotide position 3182. The leucine at codon 1061 is replaced by proline, an amino acid with similar properties. This variant has been previously reported in at least one family with multiple individuals affected with Hirschsprung disease (Geneste O et al. Hum. Mol. Genet., 1999 Oct;8:1989-99, Hofstra RM et al. Hum Mutat, 2000;15:418-29). In addition, the variant has been reported to result in a partial reduction in RET activity, demonstrating reduced binding to Shc, FRS2, and IRS-1, resulting in impaired downstream signaling as assessed in cell lines in-vitro. However, these functional studies were performed in cells also expressing the known constitutively active mutation p.C634R, therefore the clinical relevance of these findings is not known (Geneste O et al. Hum Mol Genet, 1999 Oct;8:1989-99, Melillo RM et al. Mol Cell Biol, 2001 Jul;21:4177-87, Melillo RM et al. Oncogene, 2001 Jan;20:209-18, Ishiguro Y et al. Endocrinology, 1999 Sep;140:3992-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Counsyl | RCV000662784 | SCV000785593 | uncertain significance | Multiple endocrine neoplasia type 2A | 2017-09-27 | criteria provided, single submitter | clinical testing | |
| Mendelics | RCV000662784 | SCV001138038 | uncertain significance | Multiple endocrine neoplasia type 2A | 2019-05-28 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV003462338 | SCV004206733 | uncertain significance | Hirschsprung disease, susceptibility to, 1 | 2023-05-19 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV004998413 | SCV005623107 | uncertain significance | not provided | 2024-02-24 | criteria provided, single submitter | clinical testing |