Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219970 | SCV000277656 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-02-14 | criteria provided, single submitter | clinical testing | The p.D631Y pathogenic mutation (also known as c.1891G>T) is located in coding exon 11 of the RET gene. This alteration results from a G to T substitution at nucleotide position 1891. The aspartic acid at codon 631 is replaced by tyrosine, an amino acid with highly dissimilar properties. This mutation has been observed in multiple individuals and families diagnosed with pheochromocytoma (PCC) and/or medullary thyroid carcinoma (MTC) (Elston MS et al. Horm Metab Res. 2012 May;44(5):339-42), including two large Korean MEN2A families (Bae SJ et al. Thyroid. 2006 Jun;16(6):609-14) and in a woman diagnosed with metastatic MTC and a PCC at age 40 who also carried two other RET missense alterations (Koch, CA et al. Exp Clin Endocrinol Diabetes. 2000;108(8):493). Elston et al. observed that patients with this mutation typically present first with PCC and MTC may occur at a later onset than reported with other RET mutations (Elston MS et al. Horm Metab Res. 2012 May;44(5):339-42). Functional studies indicate that D631Y acts as a gain-of-function mutation by inducing ligand-independent Ret dimerization, a mechanism of action established in other mutations within the extracellular domain (Asai N et al. Biochem. Biophys. Res. Commun. 1999 Feb 24; 255(3):587-90). This mutation has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (formerly categorized as Level B) (Wells SA et al. Thyroid. 2015 Jun; 25(6):567-610; Kloos RT et al. Thyroid. 2009 Jun; 19(6):565-612). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. |
| Invitae | RCV002513161 | SCV003441614 | pathogenic | Multiple endocrine neoplasia, type 2 | 2022-05-17 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 631 of the RET protein (p.Asp631Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of multiple endocrine neoplasia type 2 (PMID: 16839264). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24914). 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: "Benign"; Align-GVGD: "Class C15"). Experimental studies have shown that this missense change affects RET function (PMID: 10049754). For these reasons, this variant has been classified as Pathogenic. |