10-43113648-T-C

Position:

chr10-43113648-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_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:12

Conservation

PhyloP100: 4.95

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 links:

RET (HGNC:):

RET links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

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 Lovd as [Pathogenic].

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 id is 13929.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113648-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1852T>C	p.Cys618Arg	missense_variant	10/20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.1852T>C	p.Cys618Arg	missense_variant	10/20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249068

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134912

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 SAS 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.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 08, 2021	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 07, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 11, 2018	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. -

Multiple endocrine neoplasia type 2A

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)	May 21, 2023	- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 11, 2022	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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Feb 10, 2021	- -

Multiple endocrine neoplasia type 2B

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 03, 2020

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. -

Multiple endocrine neoplasia, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 27, 2023

For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects RET function (PMID: 7824936, 9174404, 9230192, 9879991). 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. ClinVar contains an entry for this variant (Variation ID: 13929). 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). This variant is present in population databases (rs76262710, gnomAD 0.007%). 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). -

Familial medullary thyroid carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2014

- -

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

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

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

Polyphen

0.96

D;.;D

Vest4

0.98

MutPred

0.94

Gain of disorder (P = 0.0129);.;Gain of disorder (P = 0.0129);

MVP

0.99

MPC

1.0

ClinPred

0.96

GERP RS

4.9

Varity_R

0.97

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over