10-43113655-G-C
Position:
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>C(p.Cys620Ser) 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
12
3
4
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 Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 10-43113655-G-C is Pathogenic according to our data. Variant chr10-43113655-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RET | NM_020975.6 | c.1859G>C | p.Cys620Ser | missense_variant | 10/20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RET | ENST00000355710.8 | c.1859G>C | p.Cys620Ser | missense_variant | 10/20 | 5 | NM_020975.6 | ENSP00000347942.3 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 13, 2013 | It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). The variant is located at one of the hot spots for variants associated with FMTC and MEN2A. Additionally, the variant has been identified in individuals affected with multiple endocrine neoplasia type 2 (MEN2), and familial medullary thyroid cancer (FMTC) (PMID: 20979234) (2011), 18062802 (2008), 14517954 (2003), 10549772 (1999), 9745455 (1998), 7874109 (1994)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 31, 2017 | The RET c.1859G>C, p.Cys620Ser variant (rs77503355) has been reported in the literature to be associated with multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC) and Hirshsprung's disease (Borrego 1998, Fernandez 2003, Frank-Raue 2011, Igarashi 2014, Lore 2000, Lore 2001, Machens 2008, Romeo 1998, Wells 2015). Other missense variants at this and adjacent residues have been implicated in MEN2A, FMTC and/or Hirshsprung's disease (Wells 2015). The p.Cys620Ser variant has been listed as pathogenic in ClinVar (Variation ID: 13943), considered a variant of moderate risk (Wells 2015), and not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). Based on the above information, the variant is classified as pathogenic. References: Borrego S et al. Molecular analysis of the ret and GDNF genes in a family with multiple endocrine neoplasia type 2A and Hirschsprung disease. J Clin Endocrinol Metab. 1998; 83(9):3361-4. Fernandez R et al. The RET C620S mutation causes multiple endocrine neoplasia type 2A (MEN2A) but not Hirschsprung disease (HSCR) in a family cosegregating both phenotypes. Hum Mutat. 2003; 22(5):412-5. 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; 32(1):51-8. Igarashi T et al. An extended family with familial medullary thyroid carcinoma and Hirschsprung's disease. J Nippon Med Sch. 2014; 81(2):64-9. Lore F et al. Unilateral renal agenesis in a family with medullary thyroid carcinoma. N Engl J Med. 2000; 342(16):1218-9. Lore F et al. Multiple endocrine neoplasia type 2 syndromes may be associated with renal malformations. J Intern Med. 2001; 250(1):37-42. Machens A et al. Familial prevalence and age of RET germline mutations: implications for screening. Clin Endocrinol (Oxf). 2008; 69(1):81-7. Romeo G et al. Association of multiple endocrine neoplasia type 2 and Hirschsprung disease. J Intern Med. 1998; 243(6):515-20. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015; 25(6):567-610. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2017 | The C620S missense variant in the RET gene has been reported many times in association with multiple endocrine neoplasia type 2 (MEN2), familial medullary thyroid cancer (FMTC), and Hirschsprung disease (for examples, see Schuffenecker et al., 1994; Borrego et al., 1998; Frank-Raue et al., 2011; Igarashi et al., 2014). Of note, variants involving the Cysteine codon at position 620 have been reported to be associated with a higher incidence of pheochromocytoma and hyperparathyroidism (Yip et al., 2003). Based on currently available evidence, we consider C620S to be pathogenic. - |
Multiple endocrine neoplasia, type 2 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 23, 2022 | For these reasons, this variant has been classified as Pathogenic. 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: 7874109, 8909322, 16705552, 20979234, 21765987). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects RET function (PMID: 9230192). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13943). This missense change has been observed in individuals with Hirschsprung disease and/or multiple endocrine neoplasia type 2 (PMID: 10777380, 11471675, 14517954). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 620 of the RET protein (p.Cys620Ser). - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 24, 2024 | This missense variant replaces cysteine with serine at codon 620 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in more than 10 individuals affected with medullary thyroid carcinoma, pheochromocytoma, and/or multiple endocrine neoplasia type 2A (PMID: 10777380, 14517954, 24805091, 7874109, 10549772, 10777380, 11471675, 11454140, 14517954, 18062802, 20979234, 24805091, 28946813, 29656518, 33827484, 37529773). It has been shown that this variant segregates with medullary thyroid cancer in multiple families (PMID: 10777380, 14517954, 24805091). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same codon, c.1858T>G (p.Cys620Gly), c.1858T>C (p.Cys620Arg), c.1859G>T (p.Cys620Phe), c.1859G>A (p.Cys620Tyr), and c.1860C>G (p.Cys620Trp), are well-documented pathogenic variants (ClinVar Variation ID: 24905, 13915, 13928, 13916, 13934), indicating that Cys at this position is important for RET protein function. Based on the available evidence, this variant is classified as Pathogenic. - |
MEN2 phenotype: Unclassified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 03, 2024 | Variant summary: RET c.1859G>C (p.Cys620Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248804 control chromosomes. c.1859G>C has been reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2 or Hirschsprung Disease (e.g. Schuffenecker_1994, Frank-Raue_2011, Lore_2000). These data indicate that the variant is very likely to be associated with disease. A different variant affecting the same codon has been classified as pathogenic by our lab (c.1858T>C, p.Cys620Arg), supporting the critical relevance of codon 620 to RET protein function. The following publications have been ascertained in the context of this evaluation (PMID: 20979234, 9230192, 10777380, 7874109). ClinVar contains an entry for this variant (Variation ID: 13943). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Multiple endocrine neoplasia type 2A Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jan 05, 2024 | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9230192]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22584715, 20979234, 9681852, 24805091, 25810047]. - |
Familial medullary thyroid carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2001 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2022 | The p.C620S pathogenic mutation (also known as c.1859G>C), located in coding exon 10 of the RET gene, results from a G to C substitution at nucleotide position 1859. The cysteine at codon 620 is replaced by serine, an amino acid with dissimilar properties. This alteration has been detected in multiple patients with medullary thyroid carcinoma (MTC) and segregated in a family with familial medullary thyroid carcinoma (FMTC) and Hirschsprung's disease (Schuffenecker I et al. Hum. Mol. Genet. 1994 Nov;3(11):1939-43; Igarashi T et al. J Nippon Med Sch, 2014;81:64-9; Machens A et al. Hum. Mutat., 2018 Jun;39:860-869). The American Thyroid Association provides management guidelines for individuals with mutations at codon 620 (Kloos RT et al. Thyroid. 2009 Jun;19(6):565-612). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;M
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Benign
D;D;D
Sift4G
Benign
T;D;T
Polyphen
D;.;D
Vest4
MutPred
Gain of disorder (P = 0.0024);.;Gain of disorder (P = 0.0024);
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