10-43114502-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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. C634L) 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:14
• Conservation: PhyloP100: 1.92

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 17 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 chr10-43114501-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13911.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
RET	NM_020975.6	c.1902C>G	p.Cys634Trp	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1902C>G	p.Cys634Trp	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247602 Hom.: 0 AF XY: 0.00000745 AC XY: 1 AN XY: 134212

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.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia type 2A Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 27, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2024	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]. -
Likely pathogenic, no assertion criteria provided	literature only	Database of Curated Mutations (DoCM)	May 13, 2016	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 30, 2022	PP1_strong, PP3, PP5, PM2, PM5, PS3_supporting, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 14, 2018	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. -

Multiple endocrine neoplasia type 4 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Multiple endocrine neoplasia type 2B Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Multiple endocrine neoplasia, type 1 Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Pheochromocytoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 27, 2007

- -

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 01, 2024

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. -

Medullary thyroid carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Mar 10, 2016

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2021

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. -

Thyroid tumor Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.52
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.76	T
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	D
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

Other links and lift over

dbSNP: rs77709286; hg19: chr10-43609950; COSMIC: COSV60687444;