Submissions for variant NM_020975.6(RET):c.1853G>A (p.Cys618Tyr)

dbSNP: rs79781594

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163667	SCV000214239	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing	The p.C618Y pathogenic mutation (also known as c.1853G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals diagnosed with medullary thyroid carcinoma (MTC) and/or MEN2A (Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8; Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4; Quayle FJ et al. Surgery 2007 Dec;142(6):800-5; discussion 805.e1; Zhao JQ et al. Hered Cancer Clin Pract. 2015 Jan;13(1):5). In addition, several other missense alterations that change the cysteine at codon 618 have been reported in the literature as disease-causing mutations (Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The American Thyroid Association categorizes alterations to the C618 residue, including p.C618Y, in the B-level risk group and has made mutation specific guidelines available (Kloos RT et al. Thyroid 2009 Jun; 19(6):565-612). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475953	SCV000543836	pathogenic	Multiple endocrine neoplasia, type 2	2023-11-13	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 618 of the RET protein (p.Cys618Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 2A and familial medullary thyroid cancer (PMID: 8103403, 20516206, 21765987, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24901). 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: 7824936, 9174404, 9230192, 9879991). This variant disrupts the p.Cys618 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7915165, 9384613, 9498388, 9839497, 20979234, 22068382; Invitae). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000475953	SCV001478765	pathogenic	Multiple endocrine neoplasia, type 2	2021-01-07	criteria provided, single submitter	clinical testing	Variant summary: RET c.1853G>A (p.Cys618Tyr) results in a non-conservative amino acid change located at a critical residue within the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249080 control chromosomes. c.1853G>A has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma and subsequently cited by others (example, Donis-Keller_1993, Chiefari_1998, Beldjord_1995, Kimura_1995, Landsvater_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in transforming activity of the RET proto-oncogene and reduced cell surface expression suggesting the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC (Ito_1997). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV001565486	SCV001788840	pathogenic	not provided	2023-11-30	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: increased transforming activity and homodimer formation (PMID: 9230192); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9879991, 9498388, 20979234, 23660264, 9839497, 8918855, 10490816, 7824936, 9174404, 19469690, 9384613, 7915165, 22068382, 26343386, 9699127, 7608256, 22747440, 8103403, 18063059, 20516206, 21765987, 11230481, 9761126, 31510104, 14633923, 29020875, 30666164, 26582918, 35053433, 37046785, 33827484, 32665702, 25628771, 9230192)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001565486	SCV004027570	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000423173	SCV000510467	likely pathogenic	Medullary thyroid carcinoma	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429944	SCV000510468	likely pathogenic	Multiple endocrine neoplasia type 2B	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440162	SCV000510469	likely pathogenic	Multiple endocrine neoplasia type 2A	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424049	SCV000510470	likely pathogenic	Multiple endocrine neoplasia, type 1	2016-05-13	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434317	SCV000510471	likely pathogenic	Multiple endocrine neoplasia type 4	2016-05-13	no assertion criteria provided	literature only