rs77503355
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_020975.6(RET):c.1859G>A(p.Cys620Tyr) 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. C620F) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
RET
NM_020975.6 missense
NM_020975.6 missense
Scores
13
5
1
Clinical Significance
Conservation
PhyloP100: 8.13
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 16 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr10-43113655-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 13928.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 10-43113655-G-A is Pathogenic according to our data. Variant chr10-43113655-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| RET | NM_020975.6 | c.1859G>A | p.Cys620Tyr | missense_variant | 10/20 | ENST00000355710.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| RET | ENST00000355710.8 | c.1859G>A | p.Cys620Tyr | missense_variant | 10/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 04, 2020 | The RET c.1859G>A; p.Cys620Tyr variant is published in the medical literature in individuals affected with multiple endocrine neoplasia type 2A (MEN2A) or MEN2A-associated cancers (Donis-Keller 1993, Frank-Raue 2011, Orgiana 2004). Additionally, other amino acid substitutions at this codon (Arg, Phe, and Ser) are described as causative for MEN2A, though missense variants at this codon often exhibit incomplete penetrance (Wells 2015). The p.Cys620Tyr variant is reported as pathogenic by multiple laboratories in the ClinVar database (Variation ID: 13916), and it is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 620 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Considering available information, the p.Cys620Tyr variant is considered to be pathogenic. References: Donis-Keller H et al. Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC. Hum Mol Genet. 1993 Jul;2(7):851-6. Frank-Raue K et al. Risk profiles and penetrance estimations in multiple endocrine neoplasia type 2A caused by germline RET mutations located in exon 10. Hum Mutat. 2011 Jan;32(1):51-8. Orgiana G et al. A new germline RET mutation apparently devoid of transforming activity serendipitously discovered in a patient with atrophic autoimmune thyroiditis and primary ovarian failure. J Clin Endocrinol Metab. 2004 Oct;89(10):4810-6. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 2021 | Published functional studies demonstrate a damaging effect: transforming activity, increased phosphorylation at RET p.Tyr905 (Orgiana 2004, Ercolino 2008); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 32408902, 31510104, 9820617, 14633923, 16158949, 15472167, 9681515, 26556299, 28698976, 8733882, 9174404, 21309721, 22865907, 21995290, 16411177, 12563086, 8103403, 9067749, 20979234, 18062802, 18248647) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 07, 2021 | This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. Over 90% of MEN2A and FMTC families have missense variants in one of six conserved cysteine residues at codons 609, 611, 618, 620, 630 or 634 in the extracellular cysteine-rich region (PMID 19443294). This variant is defined by the American Thyroid Association as being of moderate risk for developing MTC (PMID: 19469690, 25810047). Assessment of experimental evidence suggests this variant results in abnormal protein function. This variant activates RET protein kinase transforming capability, thereby inducing the protein's oncogenic activation (PMID 9230192, 18248647, 15472167, 9012462). This variant alters a critical location within the protein, and is expected to severely affect function and cause disease. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Aug 13, 2020 | - - |
Multiple endocrine neoplasia type 2A Pathogenic:3
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Apr 30, 2009 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 04, 2013 | - - |
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 | - - |
Aganglionic megacolon Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Apr 30, 2009 | - - |
Multiple endocrine neoplasia, type 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 620 of the RET protein (p.Cys620Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (MTC) and pheochromocytoma (PMID: 8797874, 9820617, 16322339, 16868135, 18062802, 18063059, 20979234, 26556299). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13916). 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: 9012462, 15472167). This variant disrupts the p.Cys620 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7849720, 7874109, 9146685, 9384613, 18206480, 19336503, 19826964, 24805091). 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) | May 13, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 20, 2022 | The c.1859G>A (p.C620Y) alteration is located in exon 10 (coding exon 10) of the RET gene. This alteration results from a G to A substitution at nucleotide position 1859, causing the cysteine (C) at amino acid position 620 to be replaced by a tyrosine (Y). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation has been well described in numerous individuals with familial medullary thyroid cancer (FMTC) (Donis-Keller, 1993; Schuffenecker, 1994; Fink, 1996; Frank-Raue, 2011; Schrader, 2016) and has also been described in a patient with Hirschsprung disease (Frank-Raue, 2011). Furthermore, codon 620 is a well-described mutation hotspot with numerous pathogenic alterations reported at this position (Kloos, 2009; Wells, 2015). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;D
Vest4
MutPred
Gain of loop (P = 0.0851);.;Gain of loop (P = 0.0851);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at