10-43114502-C-G

Variant names:

Variant summary

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

The NM_020975.6(RET):c.1902C>G(p.Cys634Trp) variant causes a missense change involving the alteration of a non-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. C634F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RET
NM_020975.6 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 1.92

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 chr10-43114501-G-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 10-43114502-C-G is Pathogenic according to our data. Variant chr10-43114502-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 13918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43114502-C-G is described in Lovd as [Pathogenic]. Variant chr10-43114502-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RET	NM_020975.6 link	c.1902C>G	p.Cys634Trp	missense_variant	Exon 11 of 20	ENST00000355710.8	NP_066124.1	P07949-1A0A024R7T2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RET	ENST00000355710.8 link	c.1902C>G	p.Cys634Trp	missense_variant	Exon 11 of 20	5	NM_020975.6	ENSP00000347942.3		P07949-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247602

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

May 17, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Observed in several individuals with medullary thyroid carcinoma (MTC) and/or pheochromocytoma, and has been found to segregate with disease in multiple MEN2A kindreds (Lips 1994, Punales 2003, Hedayati 2006, Paun 2013, Lang 2015, Pandit 2016); Published functional studies demonstrate a damaging effect: high transforming efficiency and clonogenic ability, constitutive activation of RET protein (Santoro 1995); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32235612, 30763276, 20516206, 26071011, 20672905, 33071967, 33125973, 11939755, 27539324, 24331334, 7907913, 28469506, 12000816, 15588376, 25795775, 18322301, 16507829, 18794325, 20979234, 17623957, 21765987, 23416954, 12788868, 8557249, 7915822, 28186607, 31263477, 31510104, 22226210, 29625052, 33450337, 14633923, 8984233, 7824936) -

Mar 14, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The RET c.1902C>G; p.Cys634Trp variant (rs77709286), along with several other variants at this position (Cys634Arg/Gly/Ser/Tyr), have been described in individuals and families affected with multiple endocrine neoplasia type IIA (MEN2A), familial medullary thyroid carcinoma (FMTC), and pheochromocytoma (Hedayati 2011, Hofstra 1996, Mulligan 1994, Neumann 2002, Punales 2003). Further, variants at this position are considered high risk for MTC and high penetrance of pheochromocytoma (Wells 2015). The p.Cys634Trp variant has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 13918) and is only observed in 1 out of 242460 alleles in the Genome Aggregation Database. The cysteine at codon 634 is highly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant to be deleterious. Further, functional studies demonstrate that this variant causes the RET protein to be constitutively activated (Santoro 1995). Based on available information, this variant is considered pathogenic. References: 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. 2011:264248. Hofstra R et al. RET mutation screening in familial cutaneous lichen amyloidosis and in skin amyloidosis associated with multiple endocrine neoplasia. J Invest Dermatol. 1996; 107(2):215-8. Mulligan L et al. Specific mutations of the RET proto-oncogene are related to disease phenotype in MEN 2A and FMTC. Nat Genet. 1994; 6(1):70-4. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 346(19):1459-66. Punales MK et al. RET codon 634 mutations in multiple endocrine neoplasia type 2: variable clinical features and clinical outcome. J Clin Endocrinol Metab. 2003; 88(6): 2644-9. Santoro M et al. Activation of RET as a dominant transforming gene by germline mutations of MEN2A and MEN2B. Science. 1995 Jan 20;267(5196):381-3. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. -

Aug 30, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_strong, PP3, PP5, PM2, PM5, PS3_supporting, PS4_moderate -

Multiple endocrine neoplasia type 2A

Pathogenic:2

Mar 07, 2024

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192, 34905813]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30763276, 7915822, 24331334, 26071011, 33827484, 25810047]. -

Sep 27, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Pheochromocytoma

Pathogenic:1

Sep 27, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Multiple endocrine neoplasia, type 2

Pathogenic:1

Jan 21, 2025

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 tryptophan, which is neutral and slightly polar, at codon 634 of the RET protein (p.Cys634Trp). This variant is present in population databases (rs77709286, gnomAD 0.003%). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2 (PMID: 11939755, 24331334). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13918). 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: 7824936). This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7907913, 12000816). 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

Dec 30, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C634W pathogenic mutation (also known as c.1902C>G), located in coding exon 11 of the RET gene, results from a C to G substitution at nucleotide position 1902. The cysteine at codon 634 is replaced by tryptophan, an amino acid with highly dissimilar properties. Codon 634 in the RET gene is a well known hot spot for pathogenic mutations, and individuals with mutations in this codon have a high risk for MEN2A related manifestations that may require surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19(6):565-612; Wells SA Jr et al. Thyroid. 2015 Jun;25(6):567-610). The p.C634W pathogenic mutation has been reported in several unrelated families diagnosed with MEN2A (Mulligan LM et al. Nat. Genet. 1994 Jan; 6(1):70-4; Hedayati M et al. J Thyroid Res 2011;264248; Pun DL et al. Chirurgia (Bucur) 2013;108(6):900-3). This pathogenic mutation has also been reported in two unrelated individuals with nonsyndromic pheochromocytomas but no other relevant family history (Neumann HP et al. N. Engl. J. Med. 2002 May; 346(19):1459-66). The p.C634W mutation has also been detected in a 23 year old female diagnosed with a unilateral pheochromocytoma as well as medullary thyroid cancer (Pandit R et al. Eur. J. Endocrinol. 2016 Oct;175:311-23). 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

0.74

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.52

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.7

M;.;M

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-7.7

D;D;D

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.97

MutPred

0.93

Gain of catalytic residue at C634 (P = 0.007);.;Gain of catalytic residue at C634 (P = 0.007);

MVP

0.98

MPC

0.90

ClinPred

1.0

GERP RS

3.6

Varity_R

0.94

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

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