rs377767397

chr10-43113628-G-Achr10-43113628-G-Cchr10-43113628-G-T

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PS1 PM1 PM2 PM5 PP3_Strong PP5_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 nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C611F) 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:9
• Conservation: PhyloP100: 8.14

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 22 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 2136858
• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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 chr10-43113628-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 24899.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	UniProt
RET	NM_020975.6	c.1832G>A	p.Cys611Tyr	missense_variant	10/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1832G>A	p.Cys611Tyr	missense_variant	10/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461072 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726764

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

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, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Nov 10, 2014	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	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. -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

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. -

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	D
BayesDel_noAF	Pathogenic	0.57
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.63	T
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	D
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

Other links and lift over

dbSNP: rs377767397; hg19: chr10-43609076;