Submissions for variant NM_020975.6(RET):c.1858T>G (p.Cys620Gly)

dbSNP: rs77316810

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001703419	SCV000234950	pathogenic	not provided	2021-04-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30624503, 20516206, 25694125, 12686527, 9067749, 15982921, 24972642, 11502806, 9223675, 8918855, 14718397, 30763276, 31447099, 18058472, 20979234, 14633923)
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000507202	SCV000605030	pathogenic	not specified	2016-11-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575015	SCV000664450	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-13	criteria provided, single submitter	clinical testing	The p.C620G pathogenic mutation (also known as c.1858T>G), located in coding exon 10 of the RET gene, results from a T to G substitution at nucleotide position 1858. The cysteine at codon 620 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation has been described in multiple families with RET-associated phenotypes (Eng C et al. Hum. Mutat. 1997; 9(2):97-109.; Raghavan R et al. Multiple endocrine neoplasia type 2A in a large family with a C620G mutation of the RET proto-oncogene: diagnostic, treatment, and ethical challenges [abstract]. In: Society for Endocrinology BES; 2014 March 24-27; Liverpool, UK; Yeganeh MZ et al. Tumour Biol. 2015 Jul; 36(7):5225-31).This mutation is located in codon 620, which encodes part of the extracellular cysteine rich domain and is a well-described mutation hotspot site. Mutations at this codon have been categorized by the American Thyroid Association as having moderate risk for MTC and is associated with a pheochromocytoma incidence rate of 13%–24% (Wells, et al. Thyroid. 2015;25(6):567-610). 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 interpreted as a disease-causing mutation.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000824755	SCV000711448	pathogenic	Multiple endocrine neoplasia, type 2; Aganglionic megacolon	2017-07-24	criteria provided, single submitter	clinical testing	The p.Cys620Gly variant in RET has been reported in at least 10 probands with R ET-associated disorders (diagnoses included medullary thyroid carcinoma (MTC), m ultiple endocrine neoplasia type 2A (MEN2A), and/or Hirschsprung disease) and se gregated with disease in at least 4 individuals from at least family (Kitamura 1 997, Niccoli-Sire 2001, Kruckeberg 2004, Frank-Raue 2011). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID# 24905) a nd was absent from large population studies. Additionally, other amino acid cha nges at this position have been reported in patients with MEN2A, and variants at cysteine residues in exon 10 or 11 of RET account for the majority of familial MTC and MEN2A cases (Hansford 2000, Kruckeberg 2004, Coyle 2014). Computational prediction tools and conservation analysis also suggest that the p.Cys620Gly var iant may impact the protein. In summary, this variant meets criteria to be class ified as pathogenic for MEN2A in an autosomal dominant manner based on presence in multiple affected individuals, segregation studies, absence from the general population, presence in a mutational hotspot and computational evidence. ACMG/AM P Criteria applied: PS4, PM1, PM2, PP3, PP1_supporting (Richards 2015).
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000709757	SCV000840055	pathogenic	Multiple endocrine neoplasia type 2A	2018-04-10	criteria provided, single submitter	clinical testing	This c.1858T>G (p.Cys620Gly) variant in the RET gene has been reported in multiple unrelated individuals with medullary thyroid carcinoma and Hurschsprung disease (PMID: 8918855, 9223675, 25694125, 20979234, 11502806) and is extremely rare in the general population. Other reports have also observed different changes at the same amino acid in patients with medullary thyroid carcinoma (PMID:7874109, 7849720). This c.1858T>G (p.Cys620Gly) variant in the RET gene is classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002513160	SCV003441640	pathogenic	Multiple endocrine neoplasia, type 2	2022-06-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 24905). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7849720, 7874109, 9146685, 9384613, 18206480, 19336503, 19826964, 24805091). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This missense change has been observed in individual(s) with Hirschsprung disease, medullary thyroid cancer, and/or pheochromocytoma (PMID: 20516206, 20979234, 25694125, 30763276). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 620 of the RET protein (p.Cys620Gly).
All of Us Research Program, National Institutes of Health	RCV002513160	SCV004814309	pathogenic	Multiple endocrine neoplasia, type 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 620 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. This variant has been reported in at least a dozen cases of sporadic and familial medullary thyroid cancer with or without pheochromocytoma and hyperparathyroidism (PMID: 9223675, 11502806, 14718397, 20516206, 20979234, 25694125, 28946813, 29579362, 35884466; DOI: 10.1210/jendso/bvab048.2029). Three other missense mutations at codon 620 are considered a moderate risk for MTC by the American Thyroid Association and approximately 10% to 20% of carriers are affected with pheochromocytoma and hyperparathyroidism (PMID: 25810047). This codon, cysteine 620, is considered a RET mutational hotspot observed in MEN2 disease and sporadic medullary thyroid carcinoma (PMID: 33603219). Five other protein changes at this codon from six different single-nucleotide substitutions have been reported as disease-causing in ClinVar (variation ID: 13915, 13916, 13928, 13934, 13943, 38602). 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.
PreventionGenetics, part of Exact Sciences	RCV004724753	SCV005335884	pathogenic	RET-related disorder	2024-06-28	no assertion criteria provided	clinical testing	The RET c.1858T>G variant is predicted to result in the amino acid substitution p.Cys620Gly. This variant has been reported in multiple individuals with RET-associated phenotypes including medullary thyroid carcinoma, multiple endocrine neoplasia type 2A, and Hirschsprung disease (Romei C et al. 2010. PubMed ID: 20516206; Maciel RMB et al. 2019. PubMed ID: 30763276; Frank-Raue K et al. 2011. PubMed ID: 20979234; Eng et al. 1997. PubMed ID: 9067749; Niccoli-Sire P et al. 2001. PubMed ID: 11502806; Kruckeberg KE et al. 2004. PubMed ID: 14718397). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/24905/). This variant is interpreted as pathogenic.