Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Myriad Genetics, |
RCV003316935 | SCV004018409 | pathogenic | Multiple endocrine neoplasia type 2A | 2023-03-22 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16736292, 9111992, 9263528, 12116277, 15855933, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 32546069, 9242375]. |
| All of Us Research Program, |
RCV004009734 | SCV004829682 | likely pathogenic | Multiple endocrine neoplasia, type 2 | 2023-08-08 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 768 of the RET protein. The variant is a multi-nucleotide variant (MNV) incorporating the single nucleotide variant c.2304G>C (p.Glu768Asp) and resulting in the same protein consequence. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have found that this protein change resulted in intermediate transforming activity for inducing ectopic cellular growth ex vivo and variable activation of RET kinase activity and autophosphorylation (PMID: 9242375,10445857,14715928,17047083). However, the transforming activity of this change has been shown to increase synergistically in combination with a second in cis RET variant, p.Ala919Pro (PMID: 10445857; NM_020975.6:c.2755G>C in ClinVar). This protein change, p.Glu768Asp, has been detected in at least 8 unrelated individuals affected with MEN2 or medullary thyroid cancer, and it has been reported to segregate with disease; in one pedigree, the variant is observed with later onset clinical features than a traditional pathogenic RET variant and showed incomplete penetrance (PMID: 7845675, 9263528, 11238493, 15855933, 16736292, 17097365, 29656518). The p.Glu768Asp protein change is considered a moderate risk for medullary thyroid cancer by the American Thyroid Association (PMID: 25810047). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. |