Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000470242 | SCV000543795 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-12-30 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 217 of the RET protein (p.Ala217Asp). This variant is not present in population databases (gnomAD no frequency). 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: 405525). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The aspartic acid 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 | RCV001025355 | SCV001187528 | likely benign | Hereditary cancer-predisposing syndrome | 2024-11-21 | 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. |
| St. |
RCV000470242 | SCV001737490 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2021-05-13 | criteria provided, single submitter | clinical testing | The RET c.650C>A (p.Ala217Asp) missense change is absent in gnomAD v2.1.1 and v3.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/). Seven of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in the literature in individuals with MEN2. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, BP4. |
| Gene |
RCV001570499 | SCV001794801 | uncertain significance | not provided | 2019-01-29 | criteria provided, single submitter | clinical testing | Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
| Fulgent Genetics, |
RCV002502615 | SCV002776402 | uncertain significance | Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A | 2021-10-27 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004529585 | SCV004109394 | uncertain significance | RET-related disorder | 2023-07-29 | criteria provided, single submitter | clinical testing | The RET c.650C>A variant is predicted to result in the amino acid substitution p.Ala217Asp. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/405525/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |