Submissions for variant NM_020975.6(RET):c.1901G>A (p.Cys634Tyr)

dbSNP: rs75996173

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000014924	SCV000053074	pathogenic	Multiple endocrine neoplasia type 2A	2019-07-18	criteria provided, single submitter	clinical testing	Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247574 control chromosomes. c.1901G>A has been well reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A (example Chiefari_1998, Frank-Raue_2006). These data indicate that the variant is strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV000129490	SCV000184262	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	The p.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation.
GeneDx	RCV000182582	SCV000234934	pathogenic	not provided	2023-03-24	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: high transforming ability, constitutive kinase activation (Santoro 1995, Ito 1997); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as p.(Cys380Tyr); This variant is associated with the following publications: (PMID: 12711285, 8797874, 9146685, 23723040, 19062722, 27558615, 25515555, 26254625, 29133048, 29656518, 23330657, 7835899, 21765987, 7824936, 8099202, 15858153, 8626834, 21054478, 16314641, 17895320, 24716929, 12000816, 7874109, 20080836, 26732158, 28099363, 26758973, 26572832, 26876062, 27539324, 23868299, 11987030, 30139385, 29197744, 7881414, 9230192, 28469506, 30113649, 21655256, 18063059, 12686527, 9950371, 7860065, 16099853, 11524247, 19240193, 7914213, 7491519, 12604374, 9820617, 9699127, 31062739, 30122763, 16158949, 20516206, 29625052, 31510104, 32989896, 8909322, 18096130, 9497883, 8984233, 35627249, 28152038, 30763276, 9706252, 25545346, 33340421, 33219105, 35418818, 14633923)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000476408	SCV000543790	pathogenic	Multiple endocrine neoplasia, type 2	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 7824936). This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8099202, 12000816, 21765987). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000182582	SCV000605016	pathogenic	not provided	2020-10-29	criteria provided, single submitter	clinical testing	The RET c.1901G>A;p.Cys634Tyr variant (rs75996173) is reported in the literature in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (American Thyroid Association Guidelines Task Force 2009, Punales 2003, Wells 2015). This variant is found on a single chromosome in the Genome Aggregation Database (1/247574 alleles), indicating it is not a common polymorphism. The cysteine at codon 634 is highly conserved, and other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) are considered causative for MEN2A (Wells 2015). Functional characterization of the p.Cys364Tyr variant and other missense variants at the same codon (p.Cys634Arg, p.Cys634Trp) indicates increased auto-phosphorylation and activation of downstream targets (Santoro 1995), resulting in enhanced malignant transformation of cells (Cosci 2011, Santoro 1995). Based on available information, the p.Cys634Tyr variant is considered to be pathogenic. References: American Thyroid Association Guidelines Task Force et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun;19(6):565-612. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003 Jun;88(6):2644-9. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000014924	SCV000782257	pathogenic	Multiple endocrine neoplasia type 2A	2016-11-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000014924	SCV000785514	pathogenic	Multiple endocrine neoplasia type 2A	2017-08-30	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000182582	SCV000842752	pathogenic	not provided	2021-05-14	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. The American Thyroid Association has placed this variant into the ATA-H category, formerly known as level C, for having a high risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging.
Suma Genomics	RCV000425364	SCV001847694	pathogenic	Multiple endocrine neoplasia type 2B		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000182582	SCV002047250	pathogenic	not provided	2021-05-14	criteria provided, single submitter	clinical testing	The RET c.1901G>A (p.Cys634Tyr) variant has been reported in the published literature in multiple individuals with MEN2A and/or FMTC (PMID: 7835899 (1994), 9950371 (1999), 12000816 (2002), 21765987 (2011), 25810047 (2015), 26732158 (2016), 28099363 (2017), 33167350 (2020)). A functional study found the variant has a damaging effect on RET function (PMID: 7824936 (2015)). The frequency of this variant in the general population, 0.000004 (1/247574 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000182582	SCV002522517	pathogenic	not provided	2023-02-08	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000014924	SCV002579279	pathogenic	Multiple endocrine neoplasia type 2A	2021-09-01	criteria provided, single submitter	clinical testing
Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	RCV000014924	SCV003930402	pathogenic	Multiple endocrine neoplasia type 2A	2023-05-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000425364	SCV004015290	pathogenic	Multiple endocrine neoplasia type 2B	2023-07-07	criteria provided, single submitter	clinical testing	The family RET mutation (C634Y) was detected in this blood specimen. This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Tyr). This variant is present in population databases (rs75996173, gnomAD 0.007%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2A and medullary thyroid cancer and pheochromocytoma (PMID: 2008030, 8099202, 12000816, 23723040). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13909) with 22 submissions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RET function (PMID: 7824936). This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8099202, 12000816, 21765987). Therefore, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000014924	SCV004018493	pathogenic	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 21834681]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 26732158, 17188172, 34439168, 20801952, 33827484, 25810047].
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV003989285	SCV004807294	pathogenic	Hirschsprung disease, susceptibility to, 1	2024-03-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003989285	SCV005054215	pathogenic	Hirschsprung disease, susceptibility to, 1	2023-12-29	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000014924	SCV005382535	pathogenic	Multiple endocrine neoplasia type 2A	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense c.1901G>A (p.Cys634Tyr) variant in RET gene has been reported in multiple individuals affected with RET-related disorders (Chiefari et al., 1998; Sánchez et al., 1999; Jackson et al., 2005; Valente et al., 2013; Valdés et al., 2015). It has also been observed to segregate with disease in related individuals (Valente et al., 2013). Amino acid position 634 is a well described mutation hot spot associated with Multiple endocrine neoplasia type 2A (MEN2A). Functional characterization of the p.Cys634Tyr variant and other missense variants at the same amino acid position (p.Cys634Arg, p.Cys634Trp) indicated increased auto-phosphorylation and activation of downstream targets, resulting in enhanced malignant transformation of cells (Cosci et al., 2011, Santoro et al., 1995). This variant is present with allele frequency of 0.0004% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic/ Pathogenic (multiple submissions). Multiple lines of computational evidence (Polyphen - Probably Damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid of p.Cys634Tyr in RET is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 634 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000014924	SCV000035180	pathogenic	Multiple endocrine neoplasia type 2A	2002-05-09	no assertion criteria provided	literature only
OMIM	RCV000014925	SCV000035181	pathogenic	Pheochromocytoma	2002-05-09	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421191	SCV000505641	likely pathogenic	Neoplasm	2015-07-14	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438527	SCV000510492	likely pathogenic	Medullary thyroid carcinoma	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422622	SCV000510493	likely pathogenic	Multiple endocrine neoplasia, type 1	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432822	SCV000510494	likely pathogenic	Multiple endocrine neoplasia type 4	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000014924	SCV000510495	likely pathogenic	Multiple endocrine neoplasia type 2A	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425364	SCV000510496	likely pathogenic	Multiple endocrine neoplasia type 2B	2016-05-13	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000182582	SCV001926394	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000182582	SCV001958702	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University	RCV000014925	SCV002028352	pathogenic	Pheochromocytoma	2021-10-06	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739307	SCV005361904	pathogenic	RET-related disorder	2024-06-24	no assertion criteria provided	clinical testing	The RET c.1901G>A variant is predicted to result in the amino acid substitution p.Cys634Tyr. This variant has been reported in multiple individuals with MEN2A, medullary thyroid cancer, and pheochromocytoma (Mulligan et al. 1993. PubMed ID: 8099202; Sanchez et al. 1999. PubMed ID: 9950371; Toledo et al. 2010. PubMed ID: 20080836). Functional studies have shown this variant and other amino acid changes at this position result in increased auto-phosphorylation and activation of downstream targets which enhances malignant transformation of cells (Santoro M et al. 1995. PubMed ID: 7824936; Cosci B et al. 2011. PubMed ID: 21810974). This variant is present in one individual in the gnomAD database. This variant is classified as pathogenic in ClinVar with multiple submitters in agreement (https://www.ncbi.nlm.nih.gov/clinvar/variation/13909/). We interpret this variant to be pathogenic.