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rs75076352

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_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

Scores

10
8
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 7.80
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]

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ACMG classification

Classification made for transcript

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
RETNM_020975.6 linkuse as main transcriptc.1900T>A p.Cys634Ser missense_variant 11/20 ENST00000355710.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.1900T>A p.Cys634Ser missense_variant 11/205 NM_020975.6 P4P07949-1

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
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 21, 2024This 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 submitterclinical testingAmbry GeneticsOct 05, 2023The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs75076352; hg19: chr10-43609948; COSMIC: COSV60686416; API