chr10-43113648-T-G

Variant names:

• chr10-43113648-T-G
• rs76262710
• NM_020975.6:c.1852T>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. C618S) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RET NM_020975.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:14
• Conservation: PhyloP100: 4.95
• Publications: 109 publications found

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

ACMG classification

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, 0.989
• PP5: Variant 10-43113648-T-G is Pathogenic according to our data. Variant chr10-43113648-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 13905.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	c.1852T>G	p.Cys618Gly	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.1852T>G	p.Cys618Gly	missense_variant	Exon 10 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461172 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726816

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111882

Other (OTH) AF: 0.00 AC: 0 AN: 60364

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Jul 12, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 04, 2013

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 14, 2014

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 08, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 30, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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)

Multiple endocrine neoplasia type 2A Pathogenic:4

Feb 06, 2019

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 10, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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].

Jan 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Apr 06, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hirschsprung disease, susceptibility to, 1 Pathogenic:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Multiple endocrine neoplasia, type 2 Pathogenic:1

Nov 30, 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 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’s 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.

Familial medullary thyroid carcinoma Pathogenic:1

Oct 19, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 09, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;T;T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
PhyloP100		4.9
PrimateAI	Uncertain	0.53	T
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
Vest4		0.97
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.99
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs76262710; hg19: chr10-43609096; COSMIC: COSV104412334;