- This record was updated by the submitter. Please see the current version.
NM_020975.6(RET):c.2410G>A (p.Val804Met) AND Multiple endocrine neoplasia type 2A
- Germline classification:
- Pathogenic/Likely pathogenic (7 submissions)
- Last evaluated:
- Oct 13, 2023
- 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:
- RCV000499191.19
Allele description
NM_020975.6(RET):c.2410G>A (p.Val804Met)
- 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.2410G>A (p.Val804Met)
- HGVS:
- NC_000010.11:g.43119548G>A
- NG_007489.1:g.47480G>A
- NM_000323.2:c.2410G>A
- NM_001355216.2:c.1648G>A
- NM_001406743.1:c.2410G>A
- NM_001406744.1:c.2410G>A
- NM_001406759.1:c.2410G>A
- NM_001406760.1:c.2410G>A
- NM_001406761.1:c.2281G>A
- NM_001406762.1:c.2281G>A
- NM_001406763.1:c.2275G>A
- NM_001406764.1:c.2281G>A
- NM_001406765.1:c.2275G>A
- NM_001406766.1:c.2122G>A
- NM_001406767.1:c.2122G>A
- NM_001406768.1:c.2146G>A
- NM_001406769.1:c.2014G>A
- NM_001406770.1:c.2122G>A
- NM_001406771.1:c.1972G>A
- NM_001406772.1:c.2014G>A
- NM_001406773.1:c.1972G>A
- NM_001406774.1:c.1885G>A
- NM_001406775.1:c.1684G>A
- NM_001406776.1:c.1684G>A
- NM_001406777.1:c.1684G>A
- NM_001406778.1:c.1684G>A
- NM_001406779.1:c.1513G>A
- NM_001406780.1:c.1513G>A
- NM_001406781.1:c.1513G>A
- NM_001406782.1:c.1513G>A
- NM_001406783.1:c.1384G>A
- NM_001406784.1:c.1420G>A
- NM_001406785.1:c.1393G>A
- NM_001406786.1:c.1384G>A
- NM_001406787.1:c.1378G>A
- NM_001406788.1:c.1225G>A
- NM_001406789.1:c.1225G>A
- NM_001406790.1:c.1225G>A
- NM_001406791.1:c.1105G>A
- NM_001406792.1:c.961G>A
- NM_001406793.1:c.961G>A
- NM_001406794.1:c.961G>A
- NM_020629.2:c.2410G>A
- NM_020630.7:c.2410G>A
- NM_020975.6:c.2410G>AMANE SELECT
- NP_000314.1:p.Val804Met
- NP_001342145.1:p.Val550Met
- NP_001342145.1:p.Val550Met
- NP_001393672.1:p.Val804Met
- NP_001393673.1:p.Val804Met
- NP_001393688.1:p.Val804Met
- NP_001393689.1:p.Val804Met
- NP_001393690.1:p.Val761Met
- NP_001393691.1:p.Val761Met
- NP_001393692.1:p.Val759Met
- NP_001393693.1:p.Val761Met
- NP_001393694.1:p.Val759Met
- NP_001393695.1:p.Val708Met
- NP_001393696.1:p.Val708Met
- NP_001393697.1:p.Val716Met
- NP_001393698.1:p.Val672Met
- NP_001393699.1:p.Val708Met
- NP_001393700.1:p.Val658Met
- NP_001393701.1:p.Val672Met
- NP_001393702.1:p.Val658Met
- NP_001393703.1:p.Val629Met
- NP_001393704.1:p.Val562Met
- NP_001393705.1:p.Val562Met
- NP_001393706.1:p.Val562Met
- NP_001393707.1:p.Val562Met
- NP_001393708.1:p.Val505Met
- NP_001393709.1:p.Val505Met
- NP_001393710.1:p.Val505Met
- NP_001393711.1:p.Val505Met
- NP_001393712.1:p.Val462Met
- NP_001393713.1:p.Val474Met
- NP_001393714.1:p.Val465Met
- NP_001393715.1:p.Val462Met
- NP_001393716.1:p.Val460Met
- NP_001393717.1:p.Val409Met
- NP_001393718.1:p.Val409Met
- NP_001393719.1:p.Val409Met
- NP_001393720.1:p.Val369Met
- NP_001393721.1:p.Val321Met
- NP_001393722.1:p.Val321Met
- NP_001393723.1:p.Val321Met
- NP_065680.1:p.Val804Met
- NP_065681.1:p.Val804Met
- NP_065681.1:p.Val804Met
- NP_065681.1:p.Val804Met
- NP_066124.1:p.Val804Met
- NP_066124.1:p.Val804Met
- LRG_518t1:c.2410G>A
- LRG_518t2:c.2410G>A
- LRG_518:g.47480G>A
- LRG_518p1:p.Val804Met
- LRG_518p2:p.Val804Met
- NC_000010.10:g.43614996G>A
- NM_001355216.1:c.1648G>A
- NM_020630.4:c.2410G>A
- NM_020630.6:c.2410G>A
- NM_020975.4:c.2410G>A
- NM_020975.5:c.2410G>A
- P07949:p.Val804Met
This HGVS expression did not pass validation- Protein change:
- V321M; VAL804MET
- Links:
- UniProtKB: P07949#VAR_006337; OMIM: 164761.0043; dbSNP: rs79658334
- NCBI 1000 Genomes Browser:
- rs79658334
- Molecular consequence:
- NM_000323.2:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001355216.2:c.1648G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406743.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406744.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406759.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406760.1:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406761.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406762.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406763.1:c.2275G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406764.1:c.2281G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406765.1:c.2275G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406766.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406767.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406768.1:c.2146G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406769.1:c.2014G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406770.1:c.2122G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406771.1:c.1972G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406772.1:c.2014G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406773.1:c.1972G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406774.1:c.1885G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406775.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406776.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406777.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406778.1:c.1684G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406779.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406780.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406781.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406782.1:c.1513G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406783.1:c.1384G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406784.1:c.1420G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406785.1:c.1393G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406786.1:c.1384G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406787.1:c.1378G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406788.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406789.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406790.1:c.1225G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406791.1:c.1105G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406792.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406793.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_001406794.1:c.961G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020629.2:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020630.7:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- NM_020975.6:c.2410G>A - missense variant - [Sequence Ontology: SO:0001583]
- Observations:
- 1
Condition(s)
- Name:
- Multiple endocrine neoplasia type 2A
- Synonyms:
- MULTIPLE ENDOCRINE NEOPLASIA, TYPE IIA; Sipple syndrome; MEN 2A; See all synonyms [MedGen]
- Identifiers:
- MONDO: MONDO:0008234; MeSH: D018813; MedGen: C0025268; Orphanet: 653; OMIM: 171400
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000590903 | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | no assertion criteria provided | Likely pathogenic (Jul 13, 2017) | germline | clinical testing | |
| SCV000677731 | Counsyl | criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) | Pathogenic (May 23, 2017) | unknown | clinical testing | |
| SCV000838401 | Mendelics | criteria provided, single submitter (Mendelics Assertion Criteria 2017) | Pathogenic (Jul 2, 2018) | unknown | clinical testing | |
| SCV000840056 | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (May 26, 2017) | germline | clinical testing | |
| SCV002587114 | Institute of Human Genetics, University of Leipzig Medical Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Oct 5, 2022) | unknown | clinical testing | |
| SCV004043759 | Myriad Genetics, Inc. | criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) | Pathogenic (Apr 26, 2023) | unknown | clinical testing | |
| SCV004100313 | Institute of Human Genetics, Heidelberg University | criteria provided, single submitter (ACMG Variant Classification, Richards et al., 2015, Genet Med) | Likely pathogenic (Oct 13, 2023) | paternal | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | paternal | no | not provided | 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 |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing |
| Hindu/Rajasthan | germline | yes | 1 | not provided | not provided | not provided | not provided | clinical testing |
Citations
PubMed
Romei C, Tacito A, Molinaro E, Agate L, Bottici V, Viola D, Matrone A, Biagini A, Casella F, Ciampi R, Materazzi G, Miccoli P, Torregrossa L, Ugolini C, Basolo F, Vitti P, Elisei R.
Clin Endocrinol (Oxf). 2015 Jun;82(6):892-9. doi: 10.1111/cen.12686. Epub 2014 Dec 29.
PubMed [citation]
- PMID:
- 25440022
Fattoruso O, Quadro L, Libroia A, Verga U, Lupoli G, Cascone E, Colantuoni V.
Hum Mutat. 1998;Suppl 1:S167-71. No abstract available.
PubMed [citation]
- PMID:
- 9452077
Details of each submission
From Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics, SCV000590903.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | Hindu/Rajasthan | 1 | not provided | not provided | clinical testing | not provided |
Description
This variant has been previously reported in patients from various ethnic origins with MTC and the variant has been shown to co-segregate with the disease by Romei C et al in 2015, Basaran MN et al in 2015, Fink M et al in 1996 and Fattoruso et al in 1998.This variant has been reported in the dbSNP database with identification number rs79658334 and in ExAC database with the allele frequency of 0.025%. In the Clin Var database , the clinical significance of this variant has been reported as pathogenic (RCV000148773.3) with respect to MEN2. In silico prediction tools(SIFT, LRT, MutationTaster, PolyPhen-2 and FATHMM) suggests that this variant is probably damaging to protein function.
| # | 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 Counsyl, SCV000677731.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (7) |
| # | 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 | |
From Mendelics, SCV000838401.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | 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 | unknown | unknown | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine, SCV000840056.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
This c.2410G>A (p.Val804Met) variant in the RET gene has been reported in multiple publications [PMID 8797874, 20369307, 21810974, 24361808, 23468374, 23341727, 11732489, 24336963, 19958926, 20494215]. This variant was reported in patients and segregating in multiple families with multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma [PMID 8797874, 23468374, 23341727, 20369307, 19958926, 20494215]. In vitro analysis showed that this variant affect the function of the RET protein [PMID 21810974]. A different nucleotide change (c.2410G>C), affecting the same amino acid (p.Val804Leu) has also been reported in a patient with multiple endocrine neoplasia 2 [PMID 14718397]. This variant is highly conserved and while not validated for clinical use, computer-based algorithms predict this p.Val804Met change to be deleterious. This variant has been observed in 13 heterozygous individuals in the ExAC database (http://exac.broadinstitute.org/variant/10-43614996-G-A). It is thus classified as pathogenic.
| # | 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 Institute of Human Genetics, University of Leipzig Medical Center, SCV002587114.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
_x000D_ Criteria applied: PS4, PM5_STR, PS2_MOD, PS3_SUP
| # | 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 | |
From Myriad Genetics, Inc., SCV004043759.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (14) |
Description
This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 24560924, 21810974, 21711375, 20039896, 15184865]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 15386323, 34637071, 25501606, 21134561, 10876191, 11114642, 29590403, 25810047, 20497437].
| # | 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 | |
From Institute of Human Genetics, Heidelberg University, SCV004100313.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | 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 | paternal | no | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
Last Updated: Sep 16, 2024