Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001013292 | SCV001173861 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2024-08-14 | criteria provided, single submitter | clinical testing | The p.Y606C variant (also known as c.1817A>G), located in coding exon 10 of the RET gene, results from an A to G substitution at nucleotide position 1817. The tyrosine at codon 606 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple individuals with a diagnosis of medullary thyroid cancer (MTC) (Ahmed SA et al. J Mol Diagn 2005 May;7(2):283-8, Ercolino T et al. Clin. Endocrinol. (Oxf). 2008 Aug;69(2):253-8; Wang J et al. Fam Cancer. 2016 Jan;15:99-104, Ambry internal data). Functional studies have demonstrated that this alteration leads to increased autophosphorylation and dimerization of the RET protein, and increased phosphorylation of downstream RET targets, suggesting that it is an activating mutation (Ercolino T et al. Clin. Endocrinol. (Oxf). 2008 Aug;69(2):253-8). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is likely pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. |
| Labcorp Genetics |
RCV003531905 | SCV004294353 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2022-11-25 | criteria provided, single submitter | clinical testing | 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 18248647). 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. This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 15858153, 18248647, 26254625). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24892). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 606 of the RET protein (p.Tyr606Cys). |