rs377767405

Positions:

• 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:4
• 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/exons	MANE	Protein	UniProt
RET	NM_020975.6	c.1889G>A	p.Cys630Tyr	missense_variant	11/20	ENST00000355710.8	NP_066124.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8	c.1889G>A	p.Cys630Tyr	missense_variant	11/20	5	NM_020975.6	ENSP00000347942	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Feb 24, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

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. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 24909). 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. This variant is not present in population databases (gnomAD no frequency). 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Apr 05, 2024

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

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 22, 2023

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
MutationTaster	Benign	1.0	D;D
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;