NM_020975.6:c.1852T>C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.1852T>C(p.Cys618Arg) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C618S) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.95

Publications

109 publications found

Variant links:

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]

RET Gene-Disease associations (from GenCC):

familial medullary thyroid carcinoma
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
multiple endocrine neoplasia type 2A
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P
multiple endocrine neoplasia type 2B
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
pheochromocytoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Hirschsprung disease, susceptibility to, 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Haddad syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Hirschsprung disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis, unilateral
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
bilateral renal agenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
renal agenesis
Inheritance: AR Classification: LIMITED Submitted by: G2P

RET links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 22 uncertain in NM_020975.6

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-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 10-43113648-T-C is Pathogenic according to our data. Variant chr10-43113648-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 13929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.1852T>C	p.Cys618Arg	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 link	c.1852T>C	p.Cys618Arg	missense_variant	Exon 10 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249068

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Feb 11, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The RET c.1852T>C; p.Cys618Arg variant (rs76262710) has been described in the literature in individuals and families with medullary thyroid cancer (MTC) (Hedayati 2011, Peretz 1997). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma and variants in this codon have the high risk of developing MTC (Frank-Raue 2011). This variant is reported as pathogenic by several laboratories in ClinVar (Variation ID: 13929) and is observed in the general population at a low overall frequency of 0.0004% (1/244324 alleles) in the Genome Aggregation Database. The cysteine at codon 618 is highly conserved and computational algorithms (PolyPhen2, SIFT) predict this variant to be deleterious to protein function. Based on the above information, this variant is considered pathogenic. References: 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; 32(1):51-8. Hedayati M et al. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011; Article ID 264248. Peretz H et al. Cys 618 Arg mutation in the RET proto-oncogene associated with familial medullary thyroid carcinoma and maternally transmitted Hirschsprung's disease suggesting a role for imprinting. Hum Mutat. 1997; 10(2):155-9.

Feb 08, 2021

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). The American Thyroid Association has placed this variant into the ATA-MOD category, which includes the former levels A and B, for having a moderate risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant has been reported to exhibit reduced penetrance in at least one family (PMID: 9259198). This variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant showed transforming activity, with reduced RET surface expression (PMID: 9230192, 9879991, 30884088). Computational tools predict that this variant is damaging. The variant is located in a region that is considered important for protein function and/or structure.

Oct 13, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: variant increases RET tyrosine phosphorylation activity (Chappuis-Flament et al., 1998; Okamoto et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); 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: 7849720, 7881414, 9259198, 15588376, 20516206, 27809725, 9230192, 24928018, 8675603, 24152999, 11839664, 10490816, 9745455, 9384613, 17895320, 9067749, 8626834, 20979234, 21765987, 9146685, 21325462, 21422799, 16158949, 18063059, 21054478, 15345114, 11935126, 28729773, 21575412, 26678667, 30884088, 11386462, 32948239, 29396759, 31510104, 30763276, 33340421, 14633923, 29625052, 9879991)

Jul 07, 2014

Eurofins Ntd Llc (ga)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 08, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is located at one of the hotspots associated with FMTC and MEN2A. In the published literature, the variant has been reported in multiple individuals/families with FMTC and MEN2A (PMID: 8675603 (1996), 9259198 (1997), 20979234 (2011), 21422799 (2011), 30763276 (2019)). A functional study also indicated the variant is damaging to RET protein function (PMID: 9230192 (1997)). Based on the available information, this variant is classified as pathogenic.

Multiple endocrine neoplasia type 2A

Pathogenic:3

Jan 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

May 21, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Dec 26, 2024

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, 9879991]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21422799, 20979234, 9259198, 35174786, 25810047].

Hereditary cancer-predisposing syndrome

Pathogenic:2

Feb 10, 2021

Sema4, Sema4

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

Mar 11, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C618R pathogenic mutation (also known as c.1852T>C), located in coding exon 10 of the RET gene, results from a T to C substitution at nucleotide position 1852. The cysteine at codon 618 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been identified in numerous individuals fulfilling criteria for a clinical diagnosis of multiple endocrine neoplasia type 2A (MEN2A) or familial medullary thyroid cancer (FMTC) (Ambry internal data; Romei C et al. Clin. Endocrinol. (Oxf). 2011 Feb;74:241-7; Chung YJ et al. Thyroid. 2004 Oct;14:813-8; Blaugrund JE et al. Hum. Mol. Genet. 1994 Oct;3:1895-7; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32:51-8; Zhao JQ et al. Hered Cancer Clin Pract. 2015 Jan;13:5). This alteration had been identified in six families in the literature presenting with a clinical diagnosis of MEN2A/FMTC and Hirschsprung disease (Hibi Y et al. Endocr. J. 2014;61:19-23; Mulligan LM et al. Hum Mol Genet. 1994 Dec;3:2163-7; Caron P et al. J Clin Endocrinol Metab.1996 Jul;81:2731-3; Peretz H et al. Hum Mutat. 1997;10:155-9; Pasini B et al. Surgery. 2002 Apr;131:373-81). It has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Wells SA. Thyroid. 2015 Jun;25:567-610). 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 pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.

Multiple endocrine neoplasia type 2B

Pathogenic:1

Apr 03, 2020

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3_Mod,PS4_Str,PM1,PP1_Mod,PM5_Str,PP3,PP4_Sup.

Familial medullary thyroid carcinoma

Pathogenic:1

Jan 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Multiple endocrine neoplasia, type 2

Pathogenic:1

Jan 08, 2025

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 arginine, which is basic and polar, at codon 618 of the RET protein (p.Cys618Arg). This variant is present in population databases (rs76262710, gnomAD 0.007%). This missense change has been observed in individuals with multiple endocrine neoplasia type 2, familial medullary thyroid carcinoma and Hirschsprung disease (PMID: 7849720, 7881414, 8675603, 9259198, 11935126, 14561794, 20516206, 20979234, 21422799, 21765987, 24152999, 25374962, 25628771, 25694125, 29097883). It is commonly reported in individuals of Moroccan ancestry (PMID: 7849720, 7881414, 8675603, 9259198, 11935126, 14561794, 20516206, 20979234, 21422799, 21765987, 24152999, 25374962, 25628771, 25694125, 29097883). ClinVar contains an entry for this variant (Variation ID: 13929). 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, 8099202, 8103403, 8807338, 9384613, 9498388, 9839497, 20979234, 21254918, 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.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.95

D;D;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.72

T;T;T

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M

PhyloP100

4.9

PrimateAI

Uncertain

0.64

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.015

D;D;D

Sift4G

Uncertain

0.0020

D;D;D

Vest4

0.98

ClinPred

0.96

GERP RS

4.9

Varity_R

0.97

gMVP

0.99

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over