NM_020975.6(RET):c.2370G>C (p.Leu790Phe) AND Multiple endocrine neoplasia type 2A

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Apr 18, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000014960.24

Allele description [Variation Report for NM_020975.6(RET):c.2370G>C (p.Leu790Phe)]

NM_020975.6(RET):c.2370G>C (p.Leu790Phe)

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.2370G>C (p.Leu790Phe)

Other names:

p.L790F:TTG>TTC

HGVS:

NC_000010.11:g.43118458G>C
NG_007489.1:g.46390G>C
NM_000323.2:c.2370G>C
NM_001355216.2:c.1608G>C
NM_001406743.1:c.2370G>C
NM_001406744.1:c.2370G>C
NM_001406759.1:c.2370G>C
NM_001406760.1:c.2370G>C
NM_001406761.1:c.2241G>C
NM_001406762.1:c.2241G>C
NM_001406763.1:c.2235G>C
NM_001406764.1:c.2241G>C
NM_001406765.1:c.2235G>C
NM_001406766.1:c.2082G>C
NM_001406767.1:c.2082G>C
NM_001406768.1:c.2106G>C
NM_001406769.1:c.1974G>C
NM_001406770.1:c.2082G>C
NM_001406771.1:c.1932G>C
NM_001406772.1:c.1974G>C
NM_001406773.1:c.1932G>C
NM_001406774.1:c.1845G>C
NM_001406775.1:c.1644G>C
NM_001406776.1:c.1644G>C
NM_001406777.1:c.1644G>C
NM_001406778.1:c.1644G>C
NM_001406779.1:c.1473G>C
NM_001406780.1:c.1473G>C
NM_001406781.1:c.1473G>C
NM_001406782.1:c.1473G>C
NM_001406783.1:c.1344G>C
NM_001406784.1:c.1380G>C
NM_001406785.1:c.1353G>C
NM_001406786.1:c.1344G>C
NM_001406787.1:c.1338G>C
NM_001406788.1:c.1185G>C
NM_001406789.1:c.1185G>C
NM_001406790.1:c.1185G>C
NM_001406791.1:c.1065G>C
NM_001406792.1:c.921G>C
NM_001406793.1:c.921G>C
NM_001406794.1:c.921G>C
NM_020629.2:c.2370G>C
NM_020630.7:c.2370G>C
NM_020975.6:c.2370G>CMANE SELECT
NP_000314.1:p.Leu790Phe
NP_001342145.1:p.Leu536Phe
NP_001342145.1:p.Leu536Phe
NP_001393672.1:p.Leu790Phe
NP_001393673.1:p.Leu790Phe
NP_001393688.1:p.Leu790Phe
NP_001393689.1:p.Leu790Phe
NP_001393690.1:p.Leu747Phe
NP_001393691.1:p.Leu747Phe
NP_001393692.1:p.Leu745Phe
NP_001393693.1:p.Leu747Phe
NP_001393694.1:p.Leu745Phe
NP_001393695.1:p.Leu694Phe
NP_001393696.1:p.Leu694Phe
NP_001393697.1:p.Leu702Phe
NP_001393698.1:p.Leu658Phe
NP_001393699.1:p.Leu694Phe
NP_001393700.1:p.Leu644Phe
NP_001393701.1:p.Leu658Phe
NP_001393702.1:p.Leu644Phe
NP_001393703.1:p.Leu615Phe
NP_001393704.1:p.Leu548Phe
NP_001393705.1:p.Leu548Phe
NP_001393706.1:p.Leu548Phe
NP_001393707.1:p.Leu548Phe
NP_001393708.1:p.Leu491Phe
NP_001393709.1:p.Leu491Phe
NP_001393710.1:p.Leu491Phe
NP_001393711.1:p.Leu491Phe
NP_001393712.1:p.Leu448Phe
NP_001393713.1:p.Leu460Phe
NP_001393714.1:p.Leu451Phe
NP_001393715.1:p.Leu448Phe
NP_001393716.1:p.Leu446Phe
NP_001393717.1:p.Leu395Phe
NP_001393718.1:p.Leu395Phe
NP_001393719.1:p.Leu395Phe
NP_001393720.1:p.Leu355Phe
NP_001393721.1:p.Leu307Phe
NP_001393722.1:p.Leu307Phe
NP_001393723.1:p.Leu307Phe
NP_065680.1:p.Leu790Phe
NP_065681.1:p.Leu790Phe
NP_065681.1:p.Leu790Phe
NP_065681.1:p.Leu790Phe
NP_066124.1:p.Leu790Phe
NP_066124.1:p.Leu790Phe
LRG_518t1:c.2370G>C
LRG_518t2:c.2370G>C
LRG_518:g.46390G>C
LRG_518p1:p.Leu790Phe
LRG_518p2:p.Leu790Phe
NC_000010.10:g.43613906G>C
NM_001355216.1:c.1608G>C
NM_020630.4:c.2370G>C
NM_020630.6:c.2370G>C
NM_020975.4:c.2370G>C
P07949:p.Leu790Phe

Protein change:

L307F; LEU790PHE

Links:

UniProtKB: P07949#VAR_009482; OMIM: 164761.0033; dbSNP: rs75030001

NCBI 1000 Genomes Browser:

rs75030001

Molecular consequence:

NM_000323.2:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1608G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.2241G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.2241G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.2235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.2241G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.2235G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.2082G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.2082G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.2106G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1974G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.2082G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1932G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1974G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1932G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1845G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1644G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1644G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1644G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1644G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1473G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1473G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1473G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1473G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1344G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1353G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1344G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1338G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.1185G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.1185G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.1185G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.1065G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.921G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.921G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.921G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2370G>C - missense variant - [Sequence Ontology: SO:0001583]

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

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uncharacterized protein Dmel_CG33012 [Drosophila melanogaster]
uncharacterized protein Dmel_CG33012 [Drosophila melanogaster]
gi|442623441|ref|NP_788335.2|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000035216	OMIM	no assertion criteria provided	Pathogenic (Mar 1, 1998)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000784781	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Dec 26, 2017)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23756355, 21810974, 9506724 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV004018494	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Pathogenic (Apr 18, 2023)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 28946813, 33827484, 33167350, 12490841, 12409662, 9506724, 25810047 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000035216

OMIM

no assertion criteria provided

Pathogenic
(Mar 1, 1998)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000784781

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Likely pathogenic
(Dec 26, 2017)

unknown

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf,

Citation Link,

SCV004018494

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Pathogenic
(Apr 18, 2023)

unknown

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The clinical spectrum of RET proto-oncogene mutations in codon 790.

Bihan H, Murat A, Fysekidis M, Al-Salameh A, Schwartz C, Baudin E, Thieblot P, Borson-Chazot F, Guillausseau PJ, Cardot-Bauters C, Raingeard I, Requeda E, Sadoul JL, Reznik Y; Régis Cohen for the French Group of Endocrine Tumours..

Eur J Endocrinol. 2013 Jul 29;169(3):271-6. doi: 10.1530/EJE-13-0050. Print 2013 Sep.

PubMed [citation]

PMID:: 23756355

In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer.

Cosci B, Vivaldi A, Romei C, Gemignani F, Landi S, Ciampi R, Tacito A, Molinaro E, Agate L, Bottici V, Cappagli V, Viola D, Piaggi P, Vitti P, Pinchera A, Elisei R.

Endocr Relat Cancer. 2011 Sep 20;18(5):603-12. doi: 10.1530/ERC-11-0117. Print 2011 Oct.

PubMed [citation]

PMID:: 21810974

See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000035216.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

Berndt et al. (1998) studied 181 German families with MEN2A or FMTC (155240) for mutations in the RET protooncogene. In 8 families with MEN2A or FMTC, no mutation could be detected in the cysteine-rich domain encoded in exons 10 and 11. DNA sequencing of exons 13 to 15 revealed rare noncysteine mutations in 3 families (codons 631, 768, and 844). In contrast to these rare events, heterozygous missense mutations in exon 13, codons 790 and 791, were found in 5 families (4 with MTC only; 1 family with MTC and pheochromocytoma) and 11 patients with apparently sporadic tumors. Two different leu790-to-phe mutations (TTG to TTT, TTG to TTC) and 1 tyr791-to-phe mutation (TAT to TTT) (164761.0034) were found. They concluded that codons 790 and 791 of the RET protooncogene represent a new hotspot for mutations causing MEN2A/FMTC and that 100% of the German MEN2A/FMTC families could be characterized by a mutation in the RET protooncogene.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Counsyl, SCV000784781.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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., SCV004018494.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 28946813, 33827484, 33167350, 12490841, 12409662, 9506724, 25810047].

#	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: Sep 29, 2024

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