NM_020975.6(RET):c.1826G>A (p.Cys609Tyr) AND not provided
- Germline classification:
- Pathogenic (6 submissions)
- Last evaluated:
- May 18, 2022
- Review status:
- 2 stars out of maximum of 4 starscriteria provided, multiple submitters, no conflicts
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000082049.34
Allele description [Variation Report for NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)]
NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)
- Gene:
- RET:ret proto-oncogene [Gene - OMIM - HGNC]
- Variant type:
- single nucleotide variant
- Cytogenetic location:
- 10q11.21
- Genomic location:
- Preferred name:
- NM_020975.6(RET):c.1826G>A (p.Cys609Tyr)
- Other names:
- p.C609Y:TGC>TAC
- HGVS:
- NC_000010.11:g.43113622G>A
- NG_007489.1:g.41554G>A
- NM_000323.2:c.1826G>A
- NM_001355216.2:c.1064G>A
- NM_001406743.1:c.1826G>A
- NM_001406744.1:c.1826G>A
- NM_001406759.1:c.1826G>A
- NM_001406760.1:c.1826G>A
- NM_001406761.1:c.1697G>A
- NM_001406762.1:c.1697G>A
- NM_001406763.1:c.1826G>A
- NM_001406764.1:c.1697G>A
- NM_001406765.1:c.1826G>A
- NM_001406766.1:c.1538G>A
- NM_001406767.1:c.1538G>A
- NM_001406768.1:c.1697G>A
- NM_001406769.1:c.1430G>A
- NM_001406770.1:c.1538G>A
- NM_001406771.1:c.1388G>A
- NM_001406772.1:c.1430G>A
- NM_001406773.1:c.1388G>A
- NM_001406774.1:c.1301G>A
- NM_001406775.1:c.1100G>A
- NM_001406776.1:c.1100G>A
- NM_001406777.1:c.1100G>A
- NM_001406778.1:c.1100G>A
- NM_001406779.1:c.929G>A
- NM_001406780.1:c.929G>A
- NM_001406781.1:c.929G>A
- NM_001406782.1:c.929G>A
- NM_001406783.1:c.800G>A
- NM_001406784.1:c.836G>A
- NM_001406786.1:c.800G>A
- NM_001406787.1:c.929G>A
- NM_001406788.1:c.641G>A
- NM_001406789.1:c.641G>A
- NM_001406790.1:c.641G>A
- NM_001406792.1:c.377G>A
- NM_001406793.1:c.377G>A
- NM_001406794.1:c.377G>A
- NM_020629.2:c.1826G>A
- NM_020630.7:c.1826G>A
- NM_020975.6:c.1826G>AMANE SELECT
- NP_000314.1:p.Cys609Tyr
- NP_001342145.1:p.Cys355Tyr
- NP_001342145.1:p.Cys355Tyr
- NP_001393672.1:p.Cys609Tyr
- NP_001393673.1:p.Cys609Tyr
- NP_001393688.1:p.Cys609Tyr
- NP_001393689.1:p.Cys609Tyr
- NP_001393690.1:p.Cys566Tyr
- NP_001393691.1:p.Cys566Tyr
- NP_001393692.1:p.Cys609Tyr
- NP_001393693.1:p.Cys566Tyr
- NP_001393694.1:p.Cys609Tyr
- NP_001393695.1:p.Cys513Tyr
- NP_001393696.1:p.Cys513Tyr
- NP_001393697.1:p.Cys566Tyr
- NP_001393698.1:p.Cys477Tyr
- NP_001393699.1:p.Cys513Tyr
- NP_001393700.1:p.Cys463Tyr
- NP_001393701.1:p.Cys477Tyr
- NP_001393702.1:p.Cys463Tyr
- NP_001393703.1:p.Cys434Tyr
- NP_001393704.1:p.Cys367Tyr
- NP_001393705.1:p.Cys367Tyr
- NP_001393706.1:p.Cys367Tyr
- NP_001393707.1:p.Cys367Tyr
- NP_001393708.1:p.Cys310Tyr
- NP_001393709.1:p.Cys310Tyr
- NP_001393710.1:p.Cys310Tyr
- NP_001393711.1:p.Cys310Tyr
- NP_001393712.1:p.Cys267Tyr
- NP_001393713.1:p.Cys279Tyr
- NP_001393715.1:p.Cys267Tyr
- NP_001393716.1:p.Cys310Tyr
- NP_001393717.1:p.Cys214Tyr
- NP_001393718.1:p.Cys214Tyr
- NP_001393719.1:p.Cys214Tyr
- NP_001393721.1:p.Cys126Tyr
- NP_001393722.1:p.Cys126Tyr
- NP_001393723.1:p.Cys126Tyr
- NP_065680.1:p.Cys609Tyr
- NP_065681.1:p.Cys609Tyr
- NP_065681.1:p.Cys609Tyr
- NP_065681.1:p.Cys609Tyr
- NP_066124.1:p.Cys609Tyr
- NP_066124.1:p.Cys609Tyr
- NP_066124.1:p.Cys609Tyr
- LRG_518t1:c.1826G>A
- LRG_518t2:c.1826G>A
- LRG_518:g.41554G>A
- LRG_518p1:p.Cys609Tyr
- LRG_518p2:p.Cys609Tyr
- NC_000010.10:g.43609070G>A
- NM_001355216.1:c.1064G>A
- NM_020630.4:c.1826G>A
- NM_020630.6:c.1826G>A
- NM_020975.4:c.1826G>A
- P07949:p.Cys609Tyr
This HGVS expression did not pass validation- Protein change:
- C126Y; CYS609TYR
- Links:
- UniProtKB: P07949#VAR_006306; OMIM: 164761.0029; dbSNP: rs77939446
- NCBI 1000 Genomes Browser:
- rs77939446
- Molecular consequence:
- NM_000323.2:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001355216.2:c.1064G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406743.1:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406744.1:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406759.1:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406760.1:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406761.1:c.1697G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406762.1:c.1697G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406763.1:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406764.1:c.1697G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406765.1:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406766.1:c.1538G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406767.1:c.1538G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406768.1:c.1697G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406769.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406770.1:c.1538G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406771.1:c.1388G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406772.1:c.1430G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406773.1:c.1388G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406774.1:c.1301G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406775.1:c.1100G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406776.1:c.1100G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406777.1:c.1100G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406778.1:c.1100G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406779.1:c.929G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406780.1:c.929G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406781.1:c.929G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406782.1:c.929G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406783.1:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406784.1:c.836G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406786.1:c.800G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406787.1:c.929G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406788.1:c.641G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406789.1:c.641G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406790.1:c.641G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406792.1:c.377G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406793.1:c.377G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406794.1:c.377G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020629.2:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020630.7:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020975.6:c.1826G>A - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 24
Condition(s)
- Synonyms:
- none provided
- Identifiers:
- MedGen: C3661900
Assertion and evidence details
Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
---|---|---|---|---|---|---|
SCV000225059 | Eurofins Ntd Llc (ga) | criteria provided, single submitter (EGL Classification Definitions) | Pathogenic (Jul 7, 2016) | germline | clinical testing | |
SCV000234931 | GeneDx | criteria provided, single submitter (GeneDx Variant Classification Process June 2021) | Pathogenic (Dec 16, 2021) | germline | clinical testing | |
SCV000605015 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021) | Pathogenic (Oct 7, 2020) | germline | clinical testing | |
SCV002503432 | AiLife Diagnostics, AiLife Diagnostics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jul 20, 2021) | germline | clinical testing | |
SCV002522512 | Mayo Clinic Laboratories, Mayo Clinic | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 18, 2022) | germline | clinical testing | |
SCV002774394 | Quest Diagnostics Nichols Institute San Juan Capistrano | criteria provided, single submitter (Quest Diagnostics criteria) | Pathogenic (Feb 2, 2017) | unknown | clinical testing |
Summary from all submissions
Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
---|---|---|---|---|---|---|---|---|
not provided | germline | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
not provided | germline | unknown | 23 | not provided | not provided | not provided | not provided | clinical testing |
not provided | unknown | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Medullary thyroid cancer in a patient with Hirschsprung disease with a C609Y germline RET-mutation.
de Groot JW, Sijmons RH, Links TP, Plukker JT, Hofstra RM.
J Pediatr Gastroenterol Nutr. 2005 Feb;40(2):226-9. No abstract available.
- PMID:
- 15699703
Elisei R, Tacito A, Ramone T, Ciampi R, Bottici V, Cappagli V, Viola D, Matrone A, Lorusso L, Valerio L, Giani C, Campopiano C, Prete A, Agate L, Molinaro E, Romei C.
Genes (Basel). 2019 Sep 10;10(9). doi:pii: E698. 10.3390/genes10090698.
- PMID:
- 31510104
- PMCID:
- PMC6771015
Details of each submission
From Eurofins Ntd Llc (ga), SCV000225059.5
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 7 | not provided | not provided | clinical testing | not provided |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | 7 | not provided | not provided | not provided |
From GeneDx, SCV000234931.9
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
Published functional studies demonstrate a damaging effect: significantly reduced transforming activity (Ito 1997); Not 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: 16715139, 22270996, 30763276, 20516206, 14633923, 18206480, 17021738, 18063059, 7907913, 9230192, 7849720, 15699703, 21986619, 9384613, 19472011, 27994876, 24705026, 10220148, 7595168, 18984779, 7633441, 20979234, 8901418, 12915470, 28647780, 29790872, 30927507, 31510104, 9498388, 12686527, 15531714, 10462620, 8855832, 31447099, 30787465, 33087929)
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000605015.5
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | not provided |
Description
The RET c.1826G>A; p.Cys609Tyr variant (rs77939446) has been reported in multiple patients diagnosed with multiple endocrine neoplasia type 2A (MEN2A), familial medullary thyroid carcinoma (FMTC) and Hirschsprung disease, and is considered a variant of moderate risk by the American Thyroid Association (Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13933) and is found on only one allele in the 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). Additionally, other amino acid substitutions at this codon (Arg, Gly, Phe, Ser, Trp) have been reported in individuals with MEN2A and FMTC and are considered pathogenic (Frank-Raue 2011, Paszko 2007, Romei 2010, Siegelman 1997). Based on available information, the p.Cys609Tyr variant is considered 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. 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. 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. Paszko Z et al. The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland. Cancer Invest. 2007 Dec;25(8):742-9. Romei C et al. Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes. Eur J Endocrinol. 2010 Aug;163(2):301-8. Siegelman M et al. Rapid, nonradioactive screening for mutations in exons 10, 11, and 16 of the RET protooncogene associated with inherited medullary thyroid carcinoma. Clin Chem. 1997 Mar;43(3):453-7. Wells S et al. Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma. Thyroid. 2015 25(6):567-610.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
From AiLife Diagnostics, AiLife Diagnostics, SCV002503432.1
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (13) |
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided |
From Mayo Clinic Laboratories, Mayo Clinic, SCV002522512.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | 16 | not provided | not provided | clinical testing | PubMed (1) |
Description
PP1_strong, PP4, PP5, PM1, PS3_supporting, PS4_moderate
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | germline | unknown | not provided | not provided | not provided | 16 | not provided | not provided | not provided |
From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV002774394.2
# | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
---|---|---|---|---|---|---|
1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (18) |
Description
This variant is located at one of the hot spots for pathogenic variants associated with MEN 2A and FMTC. In the published literature, this variant has been reported in individuals with MEN 2A or FMTC (PMID: 7849720 (1994), 7907913 (1994), 9146685 (1997), 18206480 (2008)). It has also been reported in individuals with Hirschsprung disease (PMID: 7633441 (1995), 9384613 (1998), 9824583 (1998)). In a functional study, this variant had a deleterious effect on RET protein function (PMID: 9230192 (1997)). Based on the available information, this variant is classified as pathogenic.
# | Sample | Method | Observation | |||||||
---|---|---|---|---|---|---|---|---|---|---|
Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
1 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided |
Last Updated: Mar 23, 2024