Submissions for variant NM_020975.6(RET):c.1597G>T (p.Gly533Cys)

dbSNP: rs75873440

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182579	SCV000234930	pathogenic	not provided	2024-02-15	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: significantly increased cell viability and reduced rate of apoptosis compared to wild-type (PMID: 21834681); 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: 25624014, 23745650, 24616773, 26678667, 26839093, 24569963, 23461807, 16649977, 22676047, 18805915, 28951487, 17704047, 28137737, 30012587, 14633923, 30763276, 33340421, 14602786, 21834681)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469127	SCV000543792	pathogenic	Multiple endocrine neoplasia, type 2	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 533 of the RET protein (p.Gly533Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A (MEN2A) (PMID: 14602786, 16649977, 18805915, 22676047, 23461807). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13950). 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. Experimental studies have shown that this missense change affects RET function (PMID: 21834681). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182579	SCV001156548	pathogenic	not provided	2023-05-05	criteria provided, single submitter	clinical testing	The RET c.1597G>T; p.Gly533Cys variant (rs75873440) is described in multiple families with medullary thyroid cancer, pheochromocytoma and multiple endocrine neoplasia type 2A (Castro 2013, Da Silva 2003, Kaldrymides 2006, Peppa 2008, Signorini 2014, Wells 2015). Functional studies show this variant increases cell growth and decreased cell death (Oliveira 2011). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 13950) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The amino acid at this position is highly conserved and computational algorithms predict this variant is deleterious (REVEL: 0.97). Considering available information, this variant is classified as pathogenic. References: Castro MR et al. Multiple endocrine neoplasia type 2A due to an exon 8 (G533C) mutation in a large North American kindred. Thyroid. 2013 Dec;23(12):1547-52. PMID: 23461807. Da Silva AM et al. A novel germ-line point mutation in RET exon 8 (Gly(533)Cys) in a large kindred with familial medullary thyroid carcinoma. J Clin Endocrinol Metab. 2003 88(11):5438-43. PMID: 14602786. Kaldrymides P et al. A rare RET gene exon 8 mutation is found in two Greek kindreds with familial medullary thyroid carcinoma: implications for screening. Clin Endocrinol (Oxf). 2006 May;64(5):561-6. PMID: 16649977 Oliveira MN et al. The RET p.G533C mutation confers predisposition to multiple endocrine neoplasia type 2A in a Brazilian kindred and is able to induce a malignant phenotype in vitro and in vivo. Thyroid. 2011 21(9):975-85. PMID: 21834681. Peppa M et al. Multiple endocrine neoplasia type 2A in two families with the familial medullary thyroid carcinoma associated G533C mutation of the RET proto-oncogene. Eur J Endocrinol. 2008 Dec;159(6):767-71. PMID: 18805915. Signorini PS et al. A ten-year clinical update of a large RET p.Gly533Cys kindred with medullary thyroid carcinoma emphasizes the need for an individualized assessment of affected relatives. Clin Endocrinol (Oxf). 2014 80(2):235-45. PMID: 23745650. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. PMID: 25810047.
Ambry Genetics	RCV001012358	SCV001172796	pathogenic	Hereditary cancer-predisposing syndrome	2023-07-14	criteria provided, single submitter	clinical testing	The p.G533C pathogenic mutation (also known as c.1597G>T), located in coding exon 8 of the RET gene, results from a G to T substitution at nucleotide position 1597. The glycine at codon 533 is replaced by cysteine, an amino acid with highly dissimilar properties. This mutation was first identified in an extensive Brazilian kindred with multiple individuals affected with medullary thyroid cancer and c-cell hyperplasia (Da Silva AM et al. J. Clin. Endocrinol. Metab. 2003 Nov; 88(11):5438-43). In a follow-up study of this kindred, one individual out of 103 carriers was found to be affected with a pheochromocytoma in addition to medullary thyroid cancer, consistent with the phenotype of MEN2A (Oliveira MN et al. Thyroid. 2011 Sep; 21(9):975-85; Signorini PS et al. Clin. Endocrinol. (Oxf) 2014 Feb; 80(2):235-45). This mutation has also been identified in multiple individuals and families of Greek ancestry affected with medullary thyroid cancer and/or pheochromocytoma, including those with the MEN2A phenotype (Kaldrymides P et al. Clin. Endocrinol. (Oxf) 2006 May; 64(5):561-6; Bethanis S et al. Hormones (Athens);6:152-6); Peppa M et al. Eur. J. Endocrinol. 2008 Dec;159:767-71; Sarika HL et al. Clin. Endocrinol. (Oxf) 2012 Dec; 77(6):857-62; Castro MR et al. Thyroid 2013 Dec; 23(12):1547-52; Saltiki K et al. Endocr Connect. 2017 Nov;6:676-684). Furthermore, functional analysis of this mutation has demonstrated that this genetic alteration confers a malignant phenotype in that mutation expressing cells were able to induce metastasis in nude mice, increase cell viability, decrease the rate of apoptosis, and decrease expression of thyroid specific genes (Oliveira MN et al. Thyroid 2011 Sep; 21(9):975-85). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000182579	SCV002774399	pathogenic	not provided	2022-04-13	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals/families with MTC and/or pheochromocytoma including those with MEN2A (PMID: 14602786 (2003), 16649977 (2006), 17704047 (2007), 18805915 (2008), 21834681 (2011), 22676047 (2012), 23461807 (2013), 24616773 (2013), 24569963 (2014), 28951487 (2017), and 28137737 (2017)). The variant has been reported to segregate with disease and has been associated with widely variable clinical presentation and age of onset (PMIDs: 14602786 (2003), 22676047 (2012), and 23461807 (2013)). Functional studies indicate that the variant is associated with increased cell proliferation and viability, anchorage-independent growth, micronuclei formation, decreased apoptosis, and induction of liver metastases (PMID: 21834681 (2011)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003335040	SCV003806553	pathogenic	Multiple endocrine neoplasia type 2A	2023-01-12	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: 14602786, 16649977, 18805915, 23461807, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 21834681].
Mayo Clinic Laboratories, Mayo Clinic	RCV000182579	SCV003929401	pathogenic	not provided	2022-12-15	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PP4, PP5, PM2, PS4_moderate
OMIM	RCV000014977	SCV000035233	pathogenic	Familial medullary thyroid carcinoma	1999-02-01	no assertion criteria provided	literature only