rs75076352

chr10-43114500-T-Achr10-43114500-T-Cchr10-43114500-T-G

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_020975.6(RET):c.1900T>A(p.Cys634Ser) 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 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. 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:2
• Conservation: PhyloP100: 7.80

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 26 ACMG points.

• PS1: Transcript NM_020975.6 (RET) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 13910
• 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, 0.984
• PP5: Variant 10-43114500-T-A is Pathogenic according to our data. Variant chr10-43114500-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 38605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43114500-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RET	NM_020975.6	c.1900T>A	p.Cys634Ser	missense_variant	11/20	ENST00000355710.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RET	ENST00000355710.8	c.1900T>A	p.Cys634Ser	missense_variant	11/20	5	NM_020975.6	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 21, 2024

This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 634 of the RET protein (p.Cys634Ser). 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 (MEN 2) and medullary thyroid carcinoma (MTC) (PMID: 9467562, 15277225, 21765987, 25143909, 25440022, 28099363). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38605). 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: 15277225, 29312610). 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: 7824936, 8103403, 8570194, 15472167, 21810974, 23210566, 23617071, 27698838). 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 05, 2023

The p.C634S pathogenic mutation (also known as c.1900T>A), located in coding exon 11 of the RET gene, results from a T to A substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in numerous families with multiple endocrine neoplasia type 2A (MEN2A) or familial medullary thyroid cancer (FMTC) and has been shown to segregate with disease in many of these families (Mulligan LM et al. Nat. Genet. 1994 Jan;6:70-4; Hedayati M et al. J Thyroid Res. 2011 Jun;2011:264248; Mahesh DM et al. Indian J Endocrinol Metab. 2014 Jul;18:516-20; Moore SW et al. J. Pediatr. Surg. 2007 Feb;42:326-32; Zhou Y et al. Clin. Endocrinol. (Oxf). 2007 Oct;67:570-6; Ambry internal data). This alteration has been shown by functional studies to lead to constitutive activation of RET tyrosine kinase and constitutive phosphorylation of MAPK (Melillo RM et al. Am. J. Pathol. 2004 Aug;165:511-21). This mutation occurs at a known hotspot and studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003; 138:409-16). Of note, the American Thyroid Association recommends that individuals with mutations in codon 634 begin surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid 2009 Jun;19(6):565-612). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.78
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.87	D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-5.9	D;D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.013	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.90		Loss of stability (P = 0.0466);.;Loss of stability (P = 0.0466);
MVP		0.97
MPC		0.72
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.70
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: rs75076352; hg19: chr10-43609948; COSMIC: COSV60686416;