Submissions for variant NM_020975.6(RET):c.2497C>T (p.Arg833Cys)

gnomAD frequency: 0.00002  dbSNP: rs377767422

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478761	SCV000568558	uncertain significance	not provided	2022-08-19	criteria provided, single submitter	clinical testing	Published functional studies demonstrate results similar to known MTC moderate-risk variants V804L and S891A, including transformation potential, tumor formation, low-level activating potential, a mild increase in kinase activity, and no invasion (Cranston et al., 2006); however, the clinical implications of these results are uncertain; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26678667, 25824727, 25810047, 19469690, 21479187, 17952863, 16469774, 25440022, 24699901, 27014708, 20301434, 24449662, 14633923, 34426522, 31510104, 32430905, 31605946, 32284345, 29590403)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529442	SCV000658454	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 833 of the RET protein (p.Arg833Cys). This variant is present in population databases (rs377767422, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of RET-related conditions (PMID: 16469774, 25440022, 32430905). ClinVar contains an entry for this variant (Variation ID: 24945). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects RET function (PMID: 16469774). 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.
Ambry Genetics	RCV000567481	SCV000674804	likely benign	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000662806	SCV000785639	uncertain significance	Multiple endocrine neoplasia type 2A	2017-10-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662806	SCV004018501	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	RCV004566753	SCV005054172	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-03-24	criteria provided, single submitter	clinical testing