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rs76262710

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.1852T>A(p.Cys618Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD Genomes 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. C618F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RET
NM_020975.6 missense

Scores

10
7
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 4.95
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 13914
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 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 chr10-43113649-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 24902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 10-43113648-T-A is Pathogenic according to our data. Variant chr10-43113648-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 38601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43113648-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.1852T>A p.Cys618Ser missense_variant 10/20 ENST00000355710.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.1852T>A p.Cys618Ser missense_variant 10/205 NM_020975.6 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249068
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134912
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.00000888
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicMay 03, 2022PP1_strong, PP3, PP4, PM1, PM2, PM5 -
Pathogenic, criteria provided, single submitterclinical testingGeneDxOct 18, 2021Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20979234, 9384613, 7849720, 22199277, 20119574, 21765987, 8557249, 12734540, 18063059, 18062802, 15858153, 22068382, 9003111, 15588376, 26254625, 9699127, 27277749, 20516206, 9498388, 26758973, 7716719, 7874109, 8849576, 31471357, 31510104, 14633923) -
Multiple endocrine neoplasia, type 2a Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMay 15, 2023Variant summary: RET c.1852T>A (p.Cys618Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Other variants at the same codon (p.Cys618Arg, p.Cys618Gly, p.Cys618Phe) have been reported in association with Multiple Endocrine Neoplasia and this codon is considered a well known hotspot suggestive of the critical relevance of this residue to RET protein function. The variant allele was found at a frequency of 4e-06 in 249068 control chromosomes. c.1852T>A has been reported in the literature in multiple individuals affected with features of Multiple Endocrine Neoplasia Type 2A (example, Decker_1998, Siegelman_1997, Biaugrand_1994, Borst_1995, Ahmed_2005). These data indicate that the variant is very likely to be associated with disease. The American Thyroid Association reports this variant as associated with an increased risk for medullary thyroid cancer and pheochromocytoma (Kloos_2009). The following publications have been ascertained in the context of this evaluation (PMID: 15858153, 7849720, 7716719, 9498388, 9230192, 9068588, 9824583, 16849421, 17590169, 17605401, 19469690). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLaboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)May 21, 2023- -
Multiple endocrine neoplasia, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 24, 2024This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Ser). This variant is present in population databases (rs76262710, gnomAD 0.0009%). A different variant (c.1853G>C) giving rise to the same protein effect has been determined to be pathogenic (PMID: 7849720, 7915165, 9384613, 9498388, 9839497, 15858153, 20119574, 20979234, 21765987, 22068382). This suggests that this variant is also likely to be causative of disease. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38601). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 7824936, 9174404, 9230192, 9879991). This variant disrupts the p.Cys618 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7915165, 9384613, 9498388, 9839497, 20979234). 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. -
RET-related condition Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesNov 04, 2023The RET c.1852T>A variant is predicted to result in the amino acid substitution p.Cys618Ser. This variant was reported in patients with multiple endocrine dysplasia type 2A and familial medullary thyroid carcinoma (Blaugrund et al. 1994. PubMed ID: 7849720; Jung et al. 2010. PubMed ID: 20119574; Romei et al. 2010. PubMed ID: 20516206; Hedayati et al. 2011. PubMed ID: 21765987; Qi et al. 2012. PubMed ID: 22068382). Of note, several missense variants affecting the same amino acid (p.Cys618Arg, p.Cys618Gly, p.Cys618Tyr, p.Cys618Phe) have also been reported to be pathogenic for multiple endocrine dysplasia type 2A and familial medullary thyroid cancer (HGMD database; Romei et al. 2010. PubMed ID: 20516206). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43609096-T-A) and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38601/). This variant is interpreted as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsApr 11, 2018The p.C618S pathogenic mutation (also known as c.1852T>A), located in coding exon 10 of the RET gene, results from a T to A substitution at nucleotide position 1852. The cysteine at codon 618 is replaced by serine, an amino acid with dissimilar properties. The American Thyroid Association reports that this alteration is associated with an increased risk for medullary thyroid cancer and pheochromocytoma (Kloos RT et al. Thyroid. 2009 Jun;19(6):565-612; Wells SA et al. Thyroid 2015 Jun;25(6):567-610). In addition, it has been identified in multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid carcinoma (FMTC) patients and families (Qi XP et al. Fam. Cancer. 2012 Mar;11(1):131-6; Jung J et al. Korean Med. Sci. 2010 Feb;25(2):226-9; Margraf R et al. Hum Mutat. 2009 Apr;30(4):548-56; Schuffenecker I et al. Hum Mol Genet. 1994 Nov;3(11):1939-43). 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
0.98
BayesDel_addAF
Pathogenic
0.53
D
BayesDel_noAF
Pathogenic
0.52
Cadd
Uncertain
25
Dann
Uncertain
0.99
DEOGEN2
Pathogenic
0.95
D;D;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.75
T;T;T
M_CAP
Pathogenic
0.80
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
0.56
T
PROVEAN
Pathogenic
-5.7
D;D;D
REVEL
Pathogenic
0.94
Sift
Uncertain
0.020
D;D;D
Sift4G
Uncertain
0.010
D;D;D
Polyphen
0.96
D;.;D
Vest4
0.98
MutPred
0.93
Gain of disorder (P = 0.0037);.;Gain of disorder (P = 0.0037);
MVP
0.99
MPC
0.37
ClinPred
0.96
D
GERP RS
4.9
Varity_R
0.89
gMVP
0.99

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: rs76262710; hg19: chr10-43609096; API