Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Mendelics | RCV000709121 | SCV000838399 | uncertain significance | Multiple endocrine neoplasia type 2A | 2018-07-02 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001351342 | SCV001545806 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-10-25 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 777 of the RET protein (p.Asn777Ser). This variant is present in population databases (rs377767415, gnomAD 0.0009%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 16384843). ClinVar contains an entry for this variant (Variation ID: 24937). 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 disruptive. Experimental studies have shown that this missense change affects RET function (PMID: 16384843). 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. |
| Molecular Genetics, |
RCV002225073 | SCV002503792 | uncertain significance | Familial medullary thyroid carcinoma | 2023-03-30 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace asparagine with serine at codon 777 of the RET protein (p.(Asn777Ser)). The asparagine residue is conserved in mammals, birds, and reptiles (100 vertebrates, UCSC), and is located in the protein tyrosine domain (UniProt). There is a small physicochemical difference between asparagine and serine. The variant is present in a single individual in a large population cohort (PM2; 1/251,332 alleles in gnomAD v2.1), and has been reported as a variant of uncertain significance in ClinVar (ID: 24937). The variant has been identified in an individual with late onset medullary thyroid cancer with limited aggressiveness (PMID: 16384843) and as an incidental finding in a single case in a paediatric cohort with various indications for testing (PMID: 31937788). The missense change has low-grade transforming potential and limited activation of RET tyrosine kinase in functional assays (PS3_Supporting; PMID: 16384843). Multiple lines of computational evidence predict a benign effect for the missense substitution, but may affect other protein features (4/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PM2, PS3_Supporting. |
| Klinik und Poliklinik für Kinderchirurgie, |
RCV001289997 | SCV001469010 | uncertain significance | Appendicitis | 2020-12-17 | no assertion criteria provided | case-control |