10-43113648-T-G

Position:

chr10-43113648-T-G

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>G(p.Cys618Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,172 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. C618R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

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-C is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 10-43113648-T-G is Pathogenic according to our data. Variant chr10-43113648-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 13905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RET	NM_020975.6 linkuse as main transcript	c.1852T>G	p.Cys618Gly	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>G	p.Cys618Gly	missense_variant	10/20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461172

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726816

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

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 30, 2023	Reported in at least one patient with MEN2A and Hirschsprung's disease (PMID: 20041006); Published functional studies demonstrate significantly reduced cell surface expression of RET (PMID: 9230192); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9067749, 31043326, 32125936, 31364476, 33603219, 30050099, 20979234, 12686527, 8626834, 9146685, 11238493, 16411177, 7835899, 8099202, 7907913, 9868860, 3078962, 18063059, 18058472, 12721726, 21422799, 27349013, 20516206, 18062802, 29396759, 16325365, 29656518, 14633923, 33827484, 24064755, 20301434, 9230192, 20041006) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 08, 2019	The RET c.1852T>G; p.Cys618Gly variant (rs76262710), also known in the literature as Cys364Gly, has been reported in several families with multiple endocrine neoplasia type 2A (MEN2A) and/or familial medullary thyroid carcinoma (FMTC) (Frank-Raue 2011, Heizmann 2006, Machens 2008, Mulligan 1993, Paszko 2007, Romei 2010, Quayle 2007). Functional assays show the variant to have transforming activity and results in decreased cell surface expression (Ito 1997). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 13905), and is absent from general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The cysteine at codon 618 is highly conserved, and computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to be damaging to the protein. Taken together, 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 Jan;32(1):51-8. Heizmann O et al. Presymptomatic thyroidectomy in multiple endocrine neoplasia 2a. Eur J Surg Oncol. 2006 Feb;32(1):98-102. 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. Machens A et al. Familial prevalence and age of RET germline mutations: implications for screening. Clin Endocrinol (Oxf). 2008 Jul;69(1):81-7. Mulligan LM et al. Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A. Nature. 1993 Jun 3;363(6428):458-60. Paszko Z et al. The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest. 2007 Dec;25(8):742-9. Romei C et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010 Aug;163(2):301-8. Quayle FJ et al. Pheochromocytoma penetrance varies by RET mutation in MEN 2A. Surgery. 2007 Dec;142(6):800-5; discussion 805.e1. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Oct 14, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 04, 2013	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with medullary thyroid cancer and pheochromocytoma (PMIDs: 8099202 (1993), 18058472 (2007), 18062802 (2008), 20516206 (2010), 24794695 (2014), 27207748 (2016), as well as in an individual with Hirschsprung's disease (PMID: 20041006 (2009)). A functional study found reduced cell surface expression (PMID: 9230192 (1997)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -

Multiple endocrine neoplasia type 2A

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1994	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 06, 2022	Variant summary: RET c.1852T>G (p.Cys618Gly) results in a non-conservative amino acid change in 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 249114 control chromosomes. c.1852T>G has been widely reported in the literature in multiple individuals and families affected with Familial Medullary Carcinoma od the Thyroid (FMTC) and features of Multiple Endocrine Neoplasia Type 2A (MEN2A) (example, Frank-Raue_1996, Machens_2001, Okeefe_1998, Mulligan_1993). 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 demonstrating an increased ability to transform NIH-3T3 cells in-vitro (example, Ito_1997). Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Feb 06, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 10, 2023	This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29656518, 20979234, 33827484, 18063059, 18058472, 24064755, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 9230192]. -

Multiple endocrine neoplasia type 2A;C0025269:Multiple endocrine neoplasia type 2B;C0031511:Pheochromocytoma;C1275808:Congenital central hypoventilation;C1833921:Familial medullary thyroid carcinoma;C3888239:Hirschsprung disease, susceptibility to, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hirschsprung disease, susceptibility to, 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Sep 22, 2024

- -

Familial medullary thyroid carcinoma

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Oct 19, 2020

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with Hirschsprung disease (MIM#142623) and medullary thyroid carcinoma (MTC) (MIM#155240), respectively (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Carriers of this variant may or may not develop MTC, it is regarded as high risk for disease onset (PMID: 29656518, OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity, however these variants are more likely to cause Hirschsprung’s disease (OMIM). 0200 - Variant is predicted to result in a missense amino acid change from cysteine to glycine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 – Two alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (Decipher). (SP) 0701 - Other missense variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple alternative missense changes at codon 618 are reported as pathogenic (ClinVar), and it is described as the most commonly mutated residue in patients with familial MTC (PMID: 29656518). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as pathogenic, and observed in many individuals with multiple endocrine neoplasia or MTC (ClinVar, PMID: 29656518, PMID: 18058472). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Multiple endocrine neoplasia, type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 24, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 618 of the RET protein (p.Cys618Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid cancer and pheochromocytoma and Hirschsprung‚Äôs disease (PMID: 8099202, 8626834, 18058472, 18062802, 18063059, 20041006, 20516206). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Cys364Gly in some of the older literature. ClinVar contains an entry for this variant (Variation ID: 13905). 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: 7835899, 7915165, 9498388, 9839497, 15858153, 20979234). 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. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2022

The p.C618G pathogenic mutation (also known as c.1852T>G), located in coding exon 10 of the RET gene, results from a T to G substitution at nucleotide position 1852. The cysteine at codon 618 is replaced by glycine, an amino acid with highly dissimilar properties. This mutation is located in the RET extracellular domain and has been associated with both MEN2A and FMTC phenotypes (Mulligan LM et al. Nature. 1993;363(6428): 458-60; Paszko Z et al. Cancer Invest. 2007;25(8):742-49; Machens A & Dralle H. Clin. Endocrinol. (Oxf) 2008 Jul;69(1):81-7; Frank-Raue K et al. Hum Mutat. 2011;32(1):51-58). Of note, this mutation is also designated as p.C364G in published literature. Several other alterations at this codon, including p.C618R, p.C618S, and p.C618F, have also been described as pathogenic. The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Wells SA et al. Thyroid. 2015 Jun; 25(6):567-610). Based on the available evidence, this alteration is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.95

D;D;.

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.75

T;T;T

M_CAP

Pathogenic

0.83

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-7.0

D;D;D

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

0.96

D;.;D

Vest4

0.97

MutPred

0.94

Gain of disorder (P = 0.0113);.;Gain of disorder (P = 0.0113);

MVP

0.99

MPC

0.73

ClinPred

0.99

GERP RS

4.9

Varity_R

0.94

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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