Submissions for variant NM_020975.6(RET):c.2530C>T (p.Arg844Trp)

dbSNP: rs377767424

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456854	SCV000543825	uncertain significance	Multiple endocrine neoplasia, type 2	2024-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 844 of the RET protein (p.Arg844Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Hirschsprung’s disease (PMID: 16818057). ClinVar contains an entry for this variant (Variation ID: 24950). An algorithm developed specifically for the RET gene suggests that this missense change is likely to be deleterious (PMID: 21479187). 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.
Counsyl	RCV000662786	SCV000785595	uncertain significance	Multiple endocrine neoplasia type 2A	2017-09-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001015858	SCV001176738	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	The p.R844W variant (also known as c.2530C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2530. The arginine at codon 844 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001588822	SCV001815392	uncertain significance	not provided	2019-09-06	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in a patient with Hirschprung disease (Kim 2006); This variant is associated with the following publications: (PMID: 16818057, 21479187)
Fulgent Genetics, Fulgent Genetics	RCV002482896	SCV002785379	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-05-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662786	SCV004018477	uncertain significance	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003460491	SCV004208681	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-02-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000456854	SCV005430386	uncertain significance	Multiple endocrine neoplasia, type 2	2024-09-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 844 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. Two other missense variants at this position, p.Arg844Leu and p.Arg844Gln, have been reported individuals affected with medullary thyroid cancer or pheochromocytoma (PMID: 9506724, 10826520, 18058472, 30877234). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.