NM_020975.6:c.1853G>C

Variant names:

• chr10-43113649-G-C
• rs79781594
• NM_020975.6:c.1853G>C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1853G>C​(p.Cys618Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C618R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:16
• Conservation: PhyloP100: 6.43

Genes affected

RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-43113648-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 10-43113649-G-C is Pathogenic according to our data. Variant chr10-43113649-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113649-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6	c.1853G>C	p.Cys618Ser	missense_variant	Exon 10 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1853G>C	p.Cys618Ser	missense_variant	Exon 10 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:9

Apr 27, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 29, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1, PP3, PP5, PM1, PM2_moderate, PM5, PS3, PS4 -

Jul 27, 2020

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2020

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Multiple endocrine neoplasia type 2A Pathogenic:3

Apr 10, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Apr 18, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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]. -

Multiple endocrine neoplasia, type 2 Pathogenic:2

Oct 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 14, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Familial medullary thyroid carcinoma Pathogenic:1

Apr 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Sep 12, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been identified in both sporadic and familial cases of medullary thyroid cancer (MTC) (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; Hedayati M et al. J. Thyroid Res. 2011 Jun;2011:264248; Qi XP et al. Fam. Cancer 2012 Mar;11(1):131-6). In another study, this mutation was identified in 7 unrelated families diagnosed with MEN2A. Of 14 total carriers in this study, 12 were diagnosed with medullary thyroid cancer and 2 with a pheochromocytoma. (Frank-Raue K et al. Hum. Mutat. 2011 Jan;32(1):51-8). This mutation 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. Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Pathogenic	0.94
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.010	D;D;D
Polyphen		0.96	D;.;D
Vest4		0.98
MutPred		0.93		Gain of disorder (P = 0.0037);.;Gain of disorder (P = 0.0037);
MVP		0.99
MPC		0.37
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.91
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs79781594; hg19: chr10-43609097;