rs377767397

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.1832G>A(p.Cys611Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,072 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. C611G) has been classified as Likely 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:10

Conservation

PhyloP100: 8.14

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:

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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 chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 10-43113628-G-A is Pathogenic according to our data. Variant chr10-43113628-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 24898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113628-G-A 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.1832G>A	p.Cys611Tyr	missense_variant	10/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 linkuse as main transcript	c.1832G>A	p.Cys611Tyr	missense_variant	10/20	5	NM_020975.6	ENSP00000347942	P4	P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461072

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726764

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 10, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2017	The C611Y missense variant in the RET gene has previously been reported in association with multiple endocrine neoplasia type 2, as well as familial medullary thyroid cancer (Landsvater et al., 1996; Frank-Raue et al., 2011; Korpershoek et al., 2014; Yeganeh et al., 2015). Functional studies show C611Y significantly decreased RET activity (Ito et al., 1997). The C611Y variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The C611Y 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Multiple missense variants at the same residue, as well as nearby residues, have been reported in the Human Gene Mutation Database in association with MEN2A-related disorders (Stenson et al., 2014). Therefore, we interpret C611Y as a pathogenic variant. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 11, 2018	The RET c.1832G>A; p.Cys611Tyr variant (rs377767397) is published in the literature in individuals with classic MEN2 with a moderate medullary thyroid carcinoma (MTC) risk level, incidence of pheochromocytoma, and incidence of hyperparathyroidism (Wells 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 24898). It is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 611 is highly conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. REFERENCES Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610 -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Multiple endocrine neoplasia, type 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 611 of the RET protein (p.Cys611Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 2 (PMID: 8765374, 11395220, 11688458, 14561794, 16712668, 17639058, 20979234, 27809725, 28099363). It is commonly reported in individuals of Danish ancestry (PMID: 8765374, 11395220, 11688458, 14561794, 16712668, 17639058, 20979234, 27809725, 28099363). This variant is also known as G2027A. ClinVar contains an entry for this variant (Variation ID: 24898). 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: 9230192). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 19, 2024	The c.1832G>A variant in the RET gene is located on exon 10 and replaces cysteine with tyrosine in codon 611 of RET protein (p.Cys611Tyr). This missense change has been observed in multiple unrelated individuals with hereditary medullary thyroid carcinoma (PMID: 29020875, 29760189, 34777782, 33827484, 30300539, 29656518, 36780067, 33397040). This variant has been reported frequently in studies conducted in Danish cohorts and is thought to be founder mutation (PMID: 29020875, 29760189). This variant has been reported to segregate with disease within members of the same family (PMID: 30300539). Late-onset and asymptomatic individuals have also been reported (PMID: 31409511, 29656518, 30300539). This variant has been classified as pathogenic by multiple submitters in ClinVar (variation ID:24898). Additionally, missense substitutions affecting the same amino acid Cys611, have been interpreted as pathogenic in ClinVar (variation ID: 24897, 24896, 24899, 13913). Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (REVEL score 0.963). This variant is extremely rare in the general population database, gnomAD (1/627966 chromosomes). For these reasons, the c.1832G>A (p.Cys611Tyr) variant in RET gene is classified as pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2024

The p.C611Y pathogenic mutation (also known as c.1832G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1832. The cysteine at codon 611 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in numerous individuals and families diagnosed with Multiple Endocrine Neoplasia Type 2A (MEN2A) or Familial Medullary Thyroid Cancer (FMTC) (Landsvater RM et al. Hum. Genet. 1996;97:11-4; Kaserer K et al. Am. J. Surg. Pathol. 2001;25:1245-51; Liu Q et al. Medicine (Baltimore). 2017 Jan;96(3):e5967; Mathiesen JS et al. Thyroid. 2017 Feb;27(2):215-223; Machens A et al. Hum Mutat. 2018 06;39:860-869; Mathiesen JS et al. Endocr Connect. 2019 Jan;8:1-7; Mathiesen JS et al. Clin Epidemiol. 2019 Jan;11:93-99; Mathiesen JS et al. Thyroid, 2019 03;29:368-377). In addition to thyroid symptoms, multiple individuals with this mutation have presented with pheochromocytoma in their seventies (Schuurman B Neth J Med 2001;58:236-40; Sjursen W et al. Fam. Cancer 2013;12(3):529-35). Several other alterations at the same codon (p.C611F, p.C611R, p.C611S, p.C611W, and p.C611G) have been described in individuals with MEN2A and FMTC. The American Thyroid Association Guidelines Task Force has provided recommendations for individuals with RET gene mutations (Kloos et al. Thyroid. 2009 June; 19(6):565-612). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.81

T;T;T

M_CAP

Pathogenic

0.73

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.7

M;.;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-7.5

D;D;D

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.99

MutPred

0.97

Loss of disorder (P = 0.0594);.;Loss of disorder (P = 0.0594);

MVP

0.98

MPC

1.0

ClinPred

1.0

GERP RS

4.9

Varity_R

0.92

gMVP

0.97

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