The p.C618S pathogenic mutation (also known as c.1853G>C), located in coding exon 10 of the RET gene, results from a G to C substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by serine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with multiple endocrine neoplasia type 2 (MEN2) (Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4; Elisei R et al. J. Clin. Endocrinol. Metab. 2007 Dec;92(12):4725-9; Jung J et al. J. Korean Med. Sci. 2010 Feb;25(2):226-9; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32(1):51-8; Hedayati M et al. J. Thyroid Res. 2011 Jun;2011:264248; Qi XP et al. Fam. Cancer 2012 Mar;11(1):131-6). This variant has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, several other pathogenic mutations have been reported at this same codon: p.C618F, p.C618G, p.C618R, and p.C618Y. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
NM_020975.6(RET):c.1853G>C (p.Cys618Ser)
Germline
Classification
Help
criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.
Pathogenic
Pathogenic (12)
Pathogenic (12)
12 out of 17 submissions contributed to this classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
17
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_020975.6(RET):c.1853G>C (p.Cys618Ser)
Variation ID: 13914 Accession: VCV000013914.40
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43113649 (GRCh38) [ NCBI UCSC ] 10: 43609097 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Apr 4, 2013 Feb 15, 2026 Dec 8, 2025 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.1853G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Cys618Ser missense NM_000323.2:c.1853G>C NP_000314.1:p.Cys618Ser missense NM_001355216.2:c.1091G>C NP_001342145.1:p.Cys364Ser missense NM_001406743.1:c.1853G>C NP_001393672.1:p.Cys618Ser missense NM_001406744.1:c.1853G>C NP_001393673.1:p.Cys618Ser missense NM_001406759.1:c.1853G>C NP_001393688.1:p.Cys618Ser missense NM_001406760.1:c.1853G>C NP_001393689.1:p.Cys618Ser missense NM_001406761.1:c.1724G>C NP_001393690.1:p.Cys575Ser missense NM_001406762.1:c.1724G>C NP_001393691.1:p.Cys575Ser missense NM_001406763.1:c.1853G>C NP_001393692.1:p.Cys618Ser missense NM_001406764.1:c.1724G>C NP_001393693.1:p.Cys575Ser missense NM_001406765.1:c.1853G>C NP_001393694.1:p.Cys618Ser missense NM_001406766.1:c.1565G>C NP_001393695.1:p.Cys522Ser missense NM_001406767.1:c.1565G>C NP_001393696.1:p.Cys522Ser missense NM_001406768.1:c.1724G>C NP_001393697.1:p.Cys575Ser missense NM_001406769.1:c.1457G>C NP_001393698.1:p.Cys486Ser missense NM_001406770.1:c.1565G>C NP_001393699.1:p.Cys522Ser missense NM_001406771.1:c.1415G>C NP_001393700.1:p.Cys472Ser missense NM_001406772.1:c.1457G>C NP_001393701.1:p.Cys486Ser missense NM_001406773.1:c.1415G>C NP_001393702.1:p.Cys472Ser missense NM_001406774.1:c.1328G>C NP_001393703.1:p.Cys443Ser missense NM_001406775.1:c.1127G>C NP_001393704.1:p.Cys376Ser missense NM_001406776.1:c.1127G>C NP_001393705.1:p.Cys376Ser missense NM_001406777.1:c.1127G>C NP_001393706.1:p.Cys376Ser missense NM_001406778.1:c.1127G>C NP_001393707.1:p.Cys376Ser missense NM_001406779.1:c.956G>C NP_001393708.1:p.Cys319Ser missense NM_001406780.1:c.956G>C NP_001393709.1:p.Cys319Ser missense NM_001406781.1:c.956G>C NP_001393710.1:p.Cys319Ser missense NM_001406782.1:c.956G>C NP_001393711.1:p.Cys319Ser missense NM_001406783.1:c.827G>C NP_001393712.1:p.Cys276Ser missense NM_001406784.1:c.863G>C NP_001393713.1:p.Cys288Ser missense NM_001406786.1:c.827G>C NP_001393715.1:p.Cys276Ser missense NM_001406787.1:c.956G>C NP_001393716.1:p.Cys319Ser missense NM_001406788.1:c.668G>C NP_001393717.1:p.Cys223Ser missense NM_001406789.1:c.668G>C NP_001393718.1:p.Cys223Ser missense NM_001406790.1:c.668G>C NP_001393719.1:p.Cys223Ser missense NM_001406792.1:c.404G>C NP_001393721.1:p.Cys135Ser missense NM_001406793.1:c.404G>C NP_001393722.1:p.Cys135Ser missense NM_001406794.1:c.404G>C NP_001393723.1:p.Cys135Ser missense NM_020629.2:c.1853G>C NP_065680.1:p.Cys618Ser missense NM_020630.7:c.1853G>C NP_065681.1:p.Cys618Ser missense NC_000010.11:g.43113649G>C NC_000010.10:g.43609097G>C NG_007489.1:g.41581G>C LRG_518:g.41581G>C LRG_518t1:c.1853G>C LRG_518p1:p.Cys618Ser LRG_518t2:c.1853G>C LRG_518p2:p.Cys618Ser P07949:p.Cys618Ser - Protein change
- C618S, C364S, C223S, C276S, C288S, C443S, C486S, C376S, C522S, C575S, C135S, C319S, C472S
- Other names
-
p.C618S:TGC>TCC
- Canonical SPDI
- NC_000010.11:43113648:G:C
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
4330 | 4466 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (1) |
no assertion criteria provided
|
Apr 1, 1994 | RCV000014934.34 | |
| Pathogenic (3) |
criteria provided, single submitter
|
Apr 18, 2023 | RCV000014933.39 | |
| Pathogenic (9) |
criteria provided, multiple submitters, no conflicts
|
May 8, 2025 | RCV000082050.38 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Dec 2, 2025 | RCV000161938.26 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Dec 8, 2025 | RCV001013348.12 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
Expand all rows
Collapse all rows
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Dec 08, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Hereditary cancer-predisposing syndrome |
Ambry Genetics
Accession: SCV001173927.5
First in ClinVar: Mar 16, 2020 Last updated: Jan 11, 2026 |
Comment:
show
The p.C618S pathogenic mutation (also known as c.1853G>C), located in coding exon 10 of the RET gene, results from a G to C substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by serine, an amino acid with dissimilar properties. This variant was reported in individual(s) with features consistent with multiple endocrine neoplasia type 2 (MEN2) (Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4; Elisei R et al. J. Clin. Endocrinol. Metab. 2007 Dec;92(12):4725-9; Jung J et al. J. Korean Med. Sci. 2010 Feb;25(2):226-9; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32(1):51-8; Hedayati M et al. J. Thyroid Res. 2011 Jun;2011:264248; Qi XP et al. Fam. Cancer 2012 Mar;11(1):131-6). This variant has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Wells SA et al. Thyroid 2015 Jun; 25(6):567-610). In addition, this alteration is predicted to be deleterious by in silico analysis. Furthermore, several other pathogenic mutations have been reported at this same codon: p.C618F, p.C618G, p.C618R, and p.C618Y. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jan 13, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Clinical Genetics and Genomics, Karolinska University Hospital
Accession: SCV001449874.1
First in ClinVar: Dec 12, 2020 Last updated: Dec 12, 2020 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Mar 14, 2024)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
|
All of Us Research Program, National Institutes of Health
Accession: SCV005430355.1
First in ClinVar: Dec 14, 2024 Last updated: Dec 14, 2024
Comment:
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more)
This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)
|
Comment:
show
This missense variant replaces cysteine with serine at codon 618 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). This variant has been reported in more than 10 individuals affected with medullary thyroid carcinoma and/or multiple endocrine neoplasia type 2A (PMID: 22068382, 7915165, 8557249, 9384613, 9498388, 20979234, 31471357). It has been shown that p.Cys618Ser segregates with disease in 9 individuals in 1 family (PMID: 22068382). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.1852T>A (p.Cys618Ser), c.1852T>C (p.Cys618Arg), c.1852T>G (p.Cys618Gly), c.1853G>T (p.Cys618Phe), and c.1853G>A (p.Cys618Tyr), are well-documented pathogenic variants (ClinVar Variation ID: 38601,13929, 13905, 24902, 24901), indicating that Cys at this position is important for RET protein function. Based on the available evidence, this variant is classified as Pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 1
Zygosity: 1 Single Heterozygote
|
|
|
Pathogenic
(Mar 07, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Multiple endocrine neoplasia, type 2
(Autosomal dominant inheritance)
|
Molecular Pathology, Peter Maccallum Cancer Centre
Accession: SCV006277504.1
First in ClinVar: Jul 13, 2025 Last updated: Jul 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Dec 02, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Multiple endocrine neoplasia, type 2 |
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000211923.13
First in ClinVar: Feb 28, 2015 Last updated: Feb 15, 2026 |
Comment:
show
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2A (PMID: 7915165, 9384613, 9498388, 9839497, 20979234, 22068382). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys364Ser. ClinVar contains an entry for this variant (Variation ID: 13914). 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: 9230192). 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: 8099202, 9498388, 9839497, 20979234, 22068382, 25628771). 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. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Jul 27, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
GeneDx
Accession: SCV000234949.16
First in ClinVar: Jul 05, 2015 Last updated: Mar 04, 2023 |
Comment:
show
Not observed in large population cohorts (Lek 2016); 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: 17895320, 29433789, 29590403, 29656518, 30273935, 7915165, 8557249, 9003111, 20979234, 26254625, 26758973, 18063059, 9384613, 28647780, 28729773, 28946813, 31510104, 30911297, 29396759) (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Apr 18, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
Multiple endocrine neoplasia type 2A |
Myriad Genetics, Inc.
Accession: SCV004018496.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
show
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7716719, 33754314, 31471357, 20979234, 22068382, 25810047]. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Jul 10, 2020)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004220035.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
Comment:
show
This variant (also known as Cys364Ser) has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is located at one of the hotspots associated with FMTC and MEN2A, and has been reported as deleterious in multiple families/individuals with FMTC and MEN2A in the published literature (PMIDs: 7915165 (1994), 9230192 (1997), 9384613 (1998), 9839497 (1998), 25694125 (2015)). Based on the available information, this variant is classified as pathogenic. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(Dec 29, 2023)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV005413940.1
First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Mar 04, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV005090845.2
First in ClinVar: Aug 04, 2024 Last updated: Mar 11, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 27, 2017)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
Eurofins Ntd Llc (ga)
Accession: SCV000225060.6
First in ClinVar: Jun 28, 2015 Last updated: Apr 13, 2025 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Number of individuals with the variant: 6
Zygosity: 6 Single Heterozygotes
Sex: mixed
|
|
|
Pathogenic
(May 08, 2025)
C
Contributing to aggregate classification
|
criteria provided, single submitter
|
not provided |
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605031.4
First in ClinVar: Sep 30, 2017 Last updated: Jan 24, 2026 |
Comment:
show
The RET c.1853G>C; p.Cys618Ser variant (rs79781594) has been described in the literature in several families with medullary thyroid cancer (MTC) and multiple endocrine neoplasia type 2A (MEN2A) (Decker 1998a, Decker 1998b, Egawa 1998, Frank-Raue 2011). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma, and variants in this codon confer a moderate risk for developing MTC (Frank-Raue 2011, Wells 2015). The variant is described in the ClinVar database (Variation ID: 13914) but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.939). This variant lies within a cysteine rich domain; pathogenic variants resulting in the loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure, resulting in aberrant activation of the RET protein (Amoresano 2005, Chappuis-Flament 1998, Ito 1997). Based on available information, this variant is classified as pathogenic. REFERNECES Amoresano A et al. Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex. Cell Signal. 2005 Jun;17(6):717-27. PMID: 15722196. Chappuis-Flament S et al. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines. Oncogene. 1998 Dec 3;17(22):2851-61. PMID: 9879991. Decker RA et al. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet. 1998 Jan;7(1):129-34. PMID: 9384613. Decker RA et al. Occurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene. J Pediatr Surg. 1998 Feb;33(2):207-14. PMID: 9498388. Egawa S et al. Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. Jpn J Clin Oncol. 1998 Oct;28(10):590-6. PMID: 9839497. Frank-Raue K et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011 Jan;32(1):51-8. PMID: 20979234. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870-2. PMID: 9230192. Wells SA et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. PMID: 25810047. (less)
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: unknown
|
|
|
Pathogenic
(Apr 10, 2017)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
Multiple endocrine neoplasia type 2A |
Counsyl
Accession: SCV000677730.3
First in ClinVar: Jun 28, 2015 Last updated: Jun 29, 2025 |
Comment:
show
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. (less)
Observation: 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
Observation 1
Collection method: clinical testing
Allele origin: unknown
Affected status: unknown
|
|
|
Pathogenic
(-)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
not provided |
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Study: VKGL Data-share Consensus
Accession: SCV001958553.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
|
|
|
Pathogenic
(Apr 01, 1994)
N
Not contributing to aggregate classification
|
no assertion criteria provided
|
MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA |
OMIM
Accession: SCV000035189.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2024 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
See 164761.0007. Xue et al. (1994) found a cys364-to-ser mutation (CYS364SER), caused by a TGC-to-TCC transversion in the RET gene, in affected members of a … (more)
See 164761.0007. Xue et al. (1994) found a cys364-to-ser mutation (CYS364SER), caused by a TGC-to-TCC transversion in the RET gene, in affected members of a family with medullary thyroid carcinoma (155240). Based on the full-length sequence of the RET gene, this mutation is cys618 to ser. (less)
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Pathogenic
(Apr 01, 1994)
N
Not contributing to aggregate classification
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no assertion criteria provided
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THYROID CARCINOMA, FAMILIAL MEDULLARY |
OMIM
Accession: SCV000035190.2
First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2024 |
Observation: 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Observation 1
Collection method: literature only
Allele origin: germline
Affected status: not provided
Comment on evidence:
See 164761.0007. Xue et al. (1994) found a cys364-to-ser mutation (CYS364SER), caused by a TGC-to-TCC transversion in the RET gene, in affected members of a … (more)
See 164761.0007. Xue et al. (1994) found a cys364-to-ser mutation (CYS364SER), caused by a TGC-to-TCC transversion in the RET gene, in affected members of a family with medullary thyroid carcinoma (155240). Based on the full-length sequence of the RET gene, this mutation is cys618 to ser. (less)
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Pathogenic
(-)
N
Not contributing to aggregate classification
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no assertion criteria provided
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not provided |
Genome Diagnostics Laboratory, University Medical Center Utrecht
Study: VKGL Data-share Consensus
Accession: SCV001927147.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021 |
Observation: 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
Observation 1
Collection method: clinical testing
Allele origin: germline
Affected status: yes
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Comment:
Comment:
This missense variant replaces cysteine with serine at codon 618 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). This variant has been reported in more than 10 individuals affected with medullary thyroid carcinoma and/or multiple endocrine neoplasia type 2A (PMID: 22068382, 7915165, 8557249, 9384613, 9498388, 20979234, 31471357). It has been shown that p.Cys618Ser segregates with disease in 9 individuals in 1 family (PMID: 22068382). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.1852T>A (p.Cys618Ser), c.1852T>C (p.Cys618Arg), c.1852T>G (p.Cys618Gly), c.1853G>T (p.Cys618Phe), and c.1853G>A (p.Cys618Tyr), are well-documented pathogenic variants (ClinVar Variation ID: 38601,13929, 13905, 24902, 24901), indicating that Cys at this position is important for RET protein function. Based on the available evidence, this variant is classified as Pathogenic.
Comment:
This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC) and multiple endocrine neoplasia type 2A (PMID: 7915165, 9384613, 9498388, 9839497, 20979234, 22068382). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys364Ser. ClinVar contains an entry for this variant (Variation ID: 13914). 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: 9230192). 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: 8099202, 9498388, 9839497, 20979234, 22068382, 25628771). 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.
Comment:
Not observed in large population cohorts (Lek 2016); 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: 17895320, 29433789, 29590403, 29656518, 30273935, 7915165, 8557249, 9003111, 20979234, 26254625, 26758973, 18063059, 9384613, 28647780, 28729773, 28946813, 31510104, 30911297, 29396759)
Comment:
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7716719, 33754314, 31471357, 20979234, 22068382, 25810047].
Comment:
This variant (also known as Cys364Ser) has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant is located at one of the hotspots associated with FMTC and MEN2A, and has been reported as deleterious in multiple families/individuals with FMTC and MEN2A in the published literature (PMIDs: 7915165 (1994), 9230192 (1997), 9384613 (1998), 9839497 (1998), 25694125 (2015)). Based on the available information, this variant is classified as pathogenic.
Comment:
PP1, PP3, PP5, PM1, PM2_moderate, PM5, PS3, PS4
Comment:
The RET c.1853G>C; p.Cys618Ser variant (rs79781594) has been described in the literature in several families with medullary thyroid cancer (MTC) and multiple endocrine neoplasia type 2A (MEN2A) (Decker 1998a, Decker 1998b, Egawa 1998, Frank-Raue 2011). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma, and variants in this codon confer a moderate risk for developing MTC (Frank-Raue 2011, Wells 2015). The variant is described in the ClinVar database (Variation ID: 13914) but is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.939). This variant lies within a cysteine rich domain; pathogenic variants resulting in the loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure, resulting in aberrant activation of the RET protein (Amoresano 2005, Chappuis-Flament 1998, Ito 1997). Based on available information, this variant is classified as pathogenic. REFERNECES Amoresano A et al. Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex. Cell Signal. 2005 Jun;17(6):717-27. PMID: 15722196. Chappuis-Flament S et al. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines. Oncogene. 1998 Dec 3;17(22):2851-61. PMID: 9879991. Decker RA et al. Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. Hum Mol Genet. 1998 Jan;7(1):129-34. PMID: 9384613. Decker RA et al. Occurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene. J Pediatr Surg. 1998 Feb;33(2):207-14. PMID: 9498388. Egawa S et al. Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. Jpn J Clin Oncol. 1998 Oct;28(10):590-6. PMID: 9839497. Frank-Raue K et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011 Jan;32(1):51-8. PMID: 20979234. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870-2. PMID: 9230192. Wells SA et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. PMID: 25810047.
Comment:
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Kidney malformations and Hirschsprung's disease in carriers of cysteine mutations in exon 10 of the RET proto-oncogene. | Machens A | Endocrine | 2021 | PMID: 33754314 |
| Unique association of multiple endocrine neoplasia 2A and congenital anomalies of the kidney and urinary tract in a child with a RET mutation. | Wood OR | BMJ case reports | 2019 | PMID: 31471357 |
| Screening of RET gene mutations in Chinese patients with medullary thyroid carcinoma and their relatives. | Wang J | Familial cancer | 2016 | PMID: 26254625 |
| Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. | Wells SA Jr | Thyroid : official journal of the American Thyroid Association | 2015 | PMID: 25810047 |
| Skewed mutational spectrum of RET proto-oncogene Exon10 in Iranian patients with medullary thyroid carcinoma. | Yeganeh MZ | Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine | 2015 | PMID: 25694125 |
| Molecular diagnosis and comprehensive treatment of multiple endocrine neoplasia type 2 in Southeastern Chinese. | Zhao JQ | Hereditary cancer in clinical practice | 2015 | PMID: 25628771 |
| RET proto-oncogene genetic screening of families with multiple endocrine neoplasia type 2 optimizes diagnostic and clinical management in China. | Qi XP | Thyroid : official journal of the American Thyroid Association | 2012 | PMID: 23210566 |
| Case report: a p.C618S RET proto-oncogene germline mutation in a large Chinese pedigree with familial medullary thyroid carcinoma. | Qi XP | Familial cancer | 2012 | PMID: 22068382 |
| Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. | Frank-Raue K | Human mutation | 2011 | PMID: 20979234 |
| Pheochromocytoma penetrance varies by RET mutation in MEN 2A. | Quayle FJ | Surgery | 2007 | PMID: 18063059 |
| RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. | Elisei R | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17895320 |
| Pyrosequencing technology as a method for the diagnosis of multiple endocrine neoplasia type 2. | Kruckeberg KE | Clinical chemistry | 2004 | PMID: 14718397 |
| Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. | Egawa S | Japanese journal of clinical oncology | 1998 | PMID: 9839497 |
| Occurrence of MEN 2a in familial Hirschsprung's disease: a new indication for genetic testing of the RET proto-oncogene. | Decker RA | Journal of pediatric surgery | 1998 | PMID: 9498388 |
| Hirschsprung disease in MEN 2A: increased spectrum of RET exon 10 genotypes and strong genotype-phenotype correlation. | Decker RA | Human molecular genetics | 1998 | PMID: 9384613 |
| Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. | Ito S | Cancer research | 1997 | PMID: 9230192 |
| Mutation analysis of the RET proto-oncogene in Dutch families with MEN 2A, MEN 2B and FMTC: two novel mutations and one de novo mutation for MEN 2A. | Landsvater RM | Human genetics | 1996 | PMID: 8557249 |
| Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease. | Borst MJ | Surgery | 1995 | PMID: 7716719 |
| Germline RET mutations in MEN 2A and FMTC and their detection by simple DNA diagnostic tests. | Xue F | Human molecular genetics | 1994 | PMID: 7915165 |
| Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. | Mulligan LM | Nature | 1993 | PMID: 8099202 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RET | - | - | - | - |
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Text-mined citations for rs79781594 ...
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Record last updated Aug 08, 2026
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.