Submissions for variant NM_020975.6(RET):c.2449C>T (p.Arg817Cys)

gnomAD frequency: 0.00002  dbSNP: rs142318626

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123311	SCV000166618	uncertain significance	Multiple endocrine neoplasia, type 2	2023-06-27	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 29625052). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 136111). This variant has not been reported in the literature in individuals affected with RET-related conditions. This variant is present in population databases (rs142318626, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 817 of the RET protein (p.Arg817Cys).
Counsyl	RCV000411874	SCV000489843	uncertain significance	Multiple endocrine neoplasia, type 2b	2016-05-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000409506	SCV000489844	uncertain significance	Multiple endocrine neoplasia, type 2a	2016-05-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000414497	SCV000490770	uncertain significance	not provided	2023-11-10	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 24336963, 29625052, 14633923)
Ambry Genetics	RCV001015577	SCV001176424	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-21	criteria provided, single submitter	clinical testing	The p.R817C variant (also known as c.2449C>T), located in coding exon 14 of the RET gene, results from a C to T substitution at nucleotide position 2449. The arginine at codon 817 is replaced by cysteine, an amino acid with highly 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. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV002466440	SCV002762740	uncertain significance	Hirschsprung disease, susceptibility to, 1	2022-06-21	criteria provided, single submitter	research	ACMG codes:PM1_Moderate, PP3_Supporting
Myriad Genetics, Inc.	RCV000409506	SCV004018490	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	RCV002466440	SCV004206712	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-06-23	criteria provided, single submitter	clinical testing