10-43113649-G-T

Position:

• chr10-43113649-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1853G>T​(p.Cys618Phe) 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. C618G) 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:5
• 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 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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-G is described in ClinVar as [Pathogenic]. Clinvar id is 13905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985
• PP5: Variant 10-43113649-G-T is Pathogenic according to our data. Variant chr10-43113649-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 24902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1853G>T	p.Cys618Phe	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1853G>T	p.Cys618Phe	missense_variant	10/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2017	The C618F variant in the RET gene has been reported previously in multiple individuals with medullary thyroid carcinoma and/or pheochromocytoma (Egawa et al., 1998; Frank-Raue et al., 2011; Kim et al., 2011), in multiple families with multiple endocrine neoplasia 2A (Edery et al., 1997; Paszko et al., 2007; Quayle et al., 2007), and was reported as a common pathogenic variant conferring moderate risk for medullary thyroid carcinoma (Wells et al., 2015). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C618F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs within a mutation hotspot at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (C618S, C618G, C618R, C618Y) have been reported in association with RET-related disorders, supporting the functional importance of this region of the protein (Donis-Keller et al., 1993; Mulligan et al., 1993; Blaugrund et al., 1994). Based on currently available evidence, we consider C618F to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 01, 2020	The RET c.1853G>T; p.Cys618Phe variant (rs79781594) is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 2A (MEN2A) or medullary thyroid cancer (MTC) (Egawa 1998, Frank-Raue 2011, Hedayati 2011, Mathiesen 2017). 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). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. 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). Indeed, other amino acid substitutions at this codon (Arg, Gly, Ser, and Tyr) have been reported in individuals with MTC or MEN2A and are considered disease-causing (Egawa 1998, Frank-Raue 2011, Hedayati 2011, Mathiesen 2017, Wells 2015). Based on available information, the p.Cys618Phe variant is considered to be pathogenic. References: 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. 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. 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. 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. 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;2011:264248. 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. Mathiesen JS et al. Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study. Thyroid. 2017 Dec;27(12):1505-1510. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. -

Multiple endocrine neoplasia type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jan 05, 2024

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29656518, 20979234, 21765987, 18058472, 18063059, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 30884088]. -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 13, 2023

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 618 of the RET protein (p.Cys618Phe). 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, 9498388, 20979234, 22068382, 25628771; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 24902). This missense change has been observed in individuals with medullary thyroid cancer (MTC) and multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid cancer (FMTC) (PMID: 8807338, 9839497, 18058472, 18063059, 21765987). This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2022

The p.C618F pathogenic mutation (also known as c.1853G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in numerous individuals and/or families fulfilling criteria for a clinical diagnosis of multiple endocrine neoplasia type 2A (MEN2A) (Kambouris M et al. Hum. Mutat.1996;8:64-70; Quayle FJ et al. Surgery, 2007 Dec;142:800-5; discussion 805.e1; Paszko Z et al. Cancer Invest., 2007 Dec;25:742-9; Hedayati M et al. J Thyroid Res. 2011 Jun;2011:264248; Kim DD et al. Thyroid. 2011 Mar;21:325-6; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32:51-8). Additionally, several other pathogenic mutations have been reported at this same codon: p.C618S, p.C618G, p.C618R, and p.C618Y. Furthermore, this mutation has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Kloos et al. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.95	D;D;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T;T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-7.0	D;D;D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.024	B;.;B
Vest4		0.94
MutPred		0.92		Loss of sheet (P = 0.0457);.;Loss of sheet (P = 0.0457);
MVP		0.96
MPC		0.41
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.92
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;