Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000687406 | SCV000814970 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2025-01-23 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 365 of the RET protein (p.Ser365Leu). This variant is present in population databases (rs763670106, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 567350). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. |
| Ambry Genetics | RCV001017260 | SCV001178311 | likely benign | Hereditary cancer-predisposing syndrome | 2021-04-06 | criteria provided, single submitter | clinical testing | This alteration is classified as likely 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. |
| Gene |
RCV003442020 | SCV004167937 | uncertain significance | not provided | 2023-10-11 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 14633923) |
| Baylor Genetics | RCV003459671 | SCV004208664 | uncertain significance | Hirschsprung disease, susceptibility to, 1 | 2023-10-10 | criteria provided, single submitter | clinical testing | |
| All of Us Research Program, |
RCV000687406 | SCV004822633 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-12-01 | criteria provided, single submitter | clinical testing | This missense variant replaces serine with leucine at codon 365 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported as a germline variant in individuals affected with RET-related cancer in the literature. This variant has been identified in 7/281958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |