NM_020975.6:c.1853G>T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong
The NM_020975.6(RET):c.1853G>T(p.Cys618Phe) 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. C618R) has been classified as Pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RET | NM_020975.6 | c.1853G>T | p.Cys618Phe | missense_variant | Exon 10 of 20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The RET c.1853G>T; p.Cys618Phe variant (rs79781594) is reported in the literature in multiple individuals and families affected with multiple endocrine neoplasia type 2A (MEN2A) or medullary thyroid cancer (MTC) (Egawa 1998, Frank-Raue 2011, Hedayati 2011, Mathiesen 2017). Individuals with this variant show age-related penetrance for MTC and pheochromocytoma, and variants in this codon confer a moderate risk for developing MTC (Frank-Raue 2011, Wells 2015). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant lies within a cysteine rich domain; pathogenic variants resulting in the loss of a cysteine residue are common in these repeats and are predicted to disrupt protein structure, resulting in aberrant activation of the RET protein (Amoresano 2005, Chappuis-Flament 1998, Ito 1997). Indeed, other amino acid substitutions at this codon (Arg, Gly, Ser, and Tyr) have been reported in individuals with MTC or MEN2A and are considered disease-causing (Egawa 1998, Frank-Raue 2011, Hedayati 2011, Mathiesen 2017, Wells 2015). Based on available information, the p.Cys618Phe variant is considered to be pathogenic. References: Amoresano A et al. Direct interactions among Ret, GDNF and GFRalpha1 molecules reveal new insights into the assembly of a functional three-protein complex. Cell Signal. 2005 Jun;17(6):717-27. Chappuis-Flament S et al. Dual effect on the RET receptor of MEN 2 mutations affecting specific extracytoplasmic cysteines. Oncogene. 1998 Dec 3;17(22):2851-61. Egawa S et al. Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. Jpn J Clin Oncol. 1998 Oct;28(10):590-6. 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. Hedayati M et al. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011;2011:264248. Ito S et al. Biological properties of Ret with cysteine mutations correlate with multiple endocrine neoplasia type 2A, familial medullary thyroid carcinoma, and Hirschsprung's disease phenotype. Cancer Res. 1997 Jul 15;57(14):2870-2. Mathiesen JS et al. Founder Effect of the RETC611Y Mutation in Multiple Endocrine Neoplasia 2A in Denmark: A Nationwide Study. Thyroid. 2017 Dec;27(12):1505-1510. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610. -
The C618F variant in the RET gene has been reported previously in multiple individuals with medullary thyroid carcinoma and/or pheochromocytoma (Egawa et al., 1998; Frank-Raue et al., 2011; Kim et al., 2011), in multiple families with multiple endocrine neoplasia 2A (Edery et al., 1997; Paszko et al., 2007; Quayle et al., 2007), and was reported as a common pathogenic variant conferring moderate risk for medullary thyroid carcinoma (Wells et al., 2015). This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The C618F variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs within a mutation hotspot at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in the same residue (C618S, C618G, C618R, C618Y) have been reported in association with RET-related disorders, supporting the functional importance of this region of the protein (Donis-Keller et al., 1993; Mulligan et al., 1993; Blaugrund et al., 1994). Based on currently available evidence, we consider C618F to be pathogenic. -
Multiple endocrine neoplasia type 2A Pathogenic:1
This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 29656518, 20979234, 21765987, 18058472, 18063059, 25810047]. Functional studies indicate this variant impacts protein function [PMID: 30884088]. -
Multiple endocrine neoplasia, type 2 Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 618 of the RET protein (p.Cys618Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid cancer (MTC) and multiple endocrine neoplasia type 2A (MEN2A) and familial medullary thyroid cancer (FMTC) (PMID: 8807338, 9839497, 18058472, 18063059, 21765987). ClinVar contains an entry for this variant (Variation ID: 24902). 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. 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, 9498388, 20979234, 22068382, 25628771; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.C618F pathogenic mutation (also known as c.1853G>T), located in coding exon 10 of the RET gene, results from a G to T substitution at nucleotide position 1853. The cysteine at codon 618 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This pathogenic mutation has been reported in numerous individuals and/or families fulfilling criteria for a clinical diagnosis of multiple endocrine neoplasia type 2A (MEN2A) (Kambouris M et al. Hum. Mutat.1996;8:64-70; Quayle FJ et al. Surgery, 2007 Dec;142:800-5; discussion 805.e1; Paszko Z et al. Cancer Invest., 2007 Dec;25:742-9; Hedayati M et al. J Thyroid Res. 2011 Jun;2011:264248; Kim DD et al. Thyroid. 2011 Mar;21:325-6; Frank-Raue K et al. Hum. Mutat. 2011 Jan;32:51-8). Additionally, several other pathogenic mutations have been reported at this same codon: p.C618S, p.C618G, p.C618R, and p.C618Y. Furthermore, this mutation has been classified as conferring "moderate risk" for MTC by the American Thyroid Association (Kloos et al. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at