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rs79781594

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_020975.6(RET):c.1853G>A(p.Cys618Tyr) variant causes a missense change. 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. C618F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

RET
NM_020975.6 missense

Scores

11
6
2

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 6.43
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 18 ACMG points.

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, 0.986
PP5
Variant 10-43113649-G-A is Pathogenic according to our data. Variant chr10-43113649-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 24901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RETNM_020975.6 linkuse as main transcriptc.1853G>A p.Cys618Tyr missense_variant 10/20 ENST00000355710.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RETENST00000355710.8 linkuse as main transcriptc.1853G>A p.Cys618Tyr missense_variant 10/205 NM_020975.6 P4P07949-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000113

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Multiple endocrine neoplasia, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingInvitaeNov 13, 2023This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 618 of the RET protein (p.Cys618Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with multiple endocrine neoplasia type 2A and familial medullary thyroid cancer (PMID: 8103403, 20516206, 21765987, 25628771). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 24901). 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, 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, 22068382; Invitae). 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. -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 07, 2021Variant summary: RET c.1853G>A (p.Cys618Tyr) results in a non-conservative amino acid change located at a critical residue within the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 249080 control chromosomes. c.1853G>A has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Familial Medullary Thyroid Carcinoma and subsequently cited by others (example, Donis-Keller_1993, Chiefari_1998, Beldjord_1995, Kimura_1995, Landsvater_1996). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in transforming activity of the RET proto-oncogene and reduced cell surface expression suggesting the potential to develop Hirschsprung's disease in addition to MEN 2A and FMTC (Ito_1997). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 16, 2020Published functional studies demonstrate a damaging effect: increased transforming activity and homodimer formation (Ito 1997); Not observed in large population cohorts (Lek et al., 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: 32665702, 14633923, 8103403, 11230481, 18063059, 20516206, 20979234, 21765987, 29020875, 31510104, 25628771, 9230192, 26582918, 30666164, 9761126, 22747440, 7608256, 9699127, 26343386, 22068382, 7915165, 9384613, 9839497, 19469690, 9174404, 9879991, 7824936, 10490816, 8918855, 23660264, 9498388) -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalAug 15, 2023- -
Multiple endocrine neoplasia type 4 Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Multiple endocrine neoplasia type 2B Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Multiple endocrine neoplasia, type 1 Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Multiple endocrine neoplasia type 2A Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Medullary thyroid carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)May 13, 2016- -
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsMar 12, 2024The p.C618Y pathogenic mutation (also known as c.1853G>A), located in coding exon 10 of the RET gene, results from a G to A substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant has been reported in multiple individuals diagnosed with medullary thyroid carcinoma (MTC) and/or MEN2A (Frank-Raue K et al. Hum Mutat. 2011 Jan;32(1):51-8; Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4; Quayle FJ et al. Surgery 2007 Dec;142(6):800-5; discussion 805.e1; Zhao JQ et al. Hered Cancer Clin Pract. 2015 Jan;13(1):5). In addition, several other missense alterations that change the cysteine at codon 618 have been reported in the literature as disease-causing mutations (Landsvater RM et al. Hum Genet. 1996 Jan;97(1):11-4). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). The American Thyroid Association categorizes alterations to the C618 residue, including p.C618Y, in the B-level risk group and has made mutation specific guidelines available (Kloos RT et al. Thyroid 2009 Jun; 19(6):565-612). 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
0.95
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.53
CADD
Pathogenic
26
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;D;.
Eigen
Uncertain
0.62
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.82
T;T;T
M_CAP
Pathogenic
0.61
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
0.65
T
PROVEAN
Pathogenic
-6.0
D;D;D
REVEL
Pathogenic
0.95
Sift
Uncertain
0.0010
D;D;D
Sift4G
Pathogenic
0.0010
D;D;D
Polyphen
0.85
P;.;P
Vest4
0.97
MutPred
0.92
Loss of methylation at K617 (P = 0.0145);.;Loss of methylation at K617 (P = 0.0145);
MVP
0.98
MPC
0.95
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.92
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: rs79781594; hg19: chr10-43609097; COSMIC: COSV60703802; API