rs377767405

Variant names:

• chr10-43114489-G-A
• rs377767405
• NM_020975.6:c.1889G>A

Your query was ambiguous. Multiple possible variants found:

• chr10-43114489-G-A
• chr10-43114489-G-C
• chr10-43114489-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):​c.1889G>A​(p.Cys630Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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. C630F) has been classified as Likely 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: 9.74

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 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, 0.988
• PP5: Variant 10-43114489-G-A is Pathogenic according to our data. Variant chr10-43114489-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 24909.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.1889G>A	p.Cys630Tyr	missense_variant	Exon 11 of 20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1889G>A	p.Cys630Tyr	missense_variant	Exon 11 of 20	5	NM_020975.6	ENSP00000347942.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

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

Mar 06, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.1889G>A p.Cys630Tyr variant (rs377767405; ClinVar Variation ID: 24909) has been described in the literature in multiple individuals and families with medullary thyroid cancer (MTC) (Kitamura 1997, Yonekawa 2007, Romei 2010, Elisei 2019) and is considered by the American Thyroid Association to impart a “moderate” lifetime risk of developing MTC (Wells 2015). It is absent from the Genome Aggregation Database (v2.1.1), 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). Computational analyses also predict that this variant is deleterious (REVEL: 0.783). Based on available information, this 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. Elisei R et al. Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. Genes (Basel). 2019 Sep 10;10(9):698. PMID: 31510104 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. Kitamura Y et al. Novel germline RET proto-oncogene mutations associated with medullary thyroid carcinoma (MTC): mutation analysis in Japanese patients with MTC. Oncogene. 1997 Jun 26;14(25):3103-6. PMID: 9223675. 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. PMID: 20516206 Wells SA et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. PMID: 25810047 Yonekawa H et al. A family of multiple endocrine neoplasia type 2A (MEN 2A) with Cys630Tyr RET germline mutation: report of a case. Endocr J. 2007 Aug;54(4):531-5. PMID: 17527003. -

Apr 05, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP3, PP4, PP5, PM1, PM2_moderate, PM5, PS4_moderate -

Multiple endocrine neoplasia type 2A Pathogenic:1

Feb 24, 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: 17527003, 9223675, 20516206, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 34905813, 10049754]. -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Feb 05, 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 tyrosine, which is neutral and polar, at codon 630 of the RET protein (p.Cys630Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid cancer (PMID: 9223675, 17527003, 21054478). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24909). 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. This variant disrupts the p.Cys630 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14561794, 15523405, 16053382, 25440022). 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

Sep 22, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C630Y pathogenic mutation (also known as c.1889G>A), located in coding exon 11 of the RET gene, results from a G to A substitution at nucleotide position 1889. The cysteine at codon 630 is replaced by tyrosine, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in multiple families diagnosed with medullary thyroid cancer (MTC) (Kitamura Y et al. Oncogene. 1997 Jun;14:3103-6; Yonekawa H et al. Endocr. J. 2007 Aug;54:531-5; Romei C et al. Clin. Endocrinol. (Oxf), 2011 Feb;74:241-7). Per the American Thyroid Association, mutations at codon 630 of the RET gene are associated with a moderate risk for developing aggressive MTC and potential screening and/or surgical options are available (Kloos et al. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). 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 interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;D;.
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0030	D;D;D
Sift4G	Benign	0.070	T;D;T
Polyphen		1.0	D;.;D
Vest4		0.98
MutPred		0.91		Gain of sheet (P = 0.0477);.;Gain of sheet (P = 0.0477);
MVP		0.98
MPC		0.91
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.76
gMVP		0.94

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: rs377767405; hg19: chr10-43609937; COSMIC: COSV104412378;