NM_020975.6(RET):c.2362A>G (p.Ile788Val) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 11, 2024
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:: RCV000800262.10

Allele description [Variation Report for NM_020975.6(RET):c.2362A>G (p.Ile788Val)]

NM_020975.6(RET):c.2362A>G (p.Ile788Val)

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.2362A>G (p.Ile788Val)

HGVS:

NC_000010.11:g.43118450A>G
NG_007489.1:g.46382A>G
NM_000323.2:c.2362A>G
NM_001355216.2:c.1600A>G
NM_001406743.1:c.2362A>G
NM_001406744.1:c.2362A>G
NM_001406759.1:c.2362A>G
NM_001406760.1:c.2362A>G
NM_001406761.1:c.2233A>G
NM_001406762.1:c.2233A>G
NM_001406763.1:c.2227A>G
NM_001406764.1:c.2233A>G
NM_001406765.1:c.2227A>G
NM_001406766.1:c.2074A>G
NM_001406767.1:c.2074A>G
NM_001406768.1:c.2098A>G
NM_001406769.1:c.1966A>G
NM_001406770.1:c.2074A>G
NM_001406771.1:c.1924A>G
NM_001406772.1:c.1966A>G
NM_001406773.1:c.1924A>G
NM_001406774.1:c.1837A>G
NM_001406775.1:c.1636A>G
NM_001406776.1:c.1636A>G
NM_001406777.1:c.1636A>G
NM_001406778.1:c.1636A>G
NM_001406779.1:c.1465A>G
NM_001406780.1:c.1465A>G
NM_001406781.1:c.1465A>G
NM_001406782.1:c.1465A>G
NM_001406783.1:c.1336A>G
NM_001406784.1:c.1372A>G
NM_001406785.1:c.1345A>G
NM_001406786.1:c.1336A>G
NM_001406787.1:c.1330A>G
NM_001406788.1:c.1177A>G
NM_001406789.1:c.1177A>G
NM_001406790.1:c.1177A>G
NM_001406791.1:c.1057A>G
NM_001406792.1:c.913A>G
NM_001406793.1:c.913A>G
NM_001406794.1:c.913A>G
NM_020629.2:c.2362A>G
NM_020630.7:c.2362A>G
NM_020975.6:c.2362A>GMANE SELECT
NP_000314.1:p.Ile788Val
NP_001342145.1:p.Ile534Val
NP_001342145.1:p.Ile534Val
NP_001393672.1:p.Ile788Val
NP_001393673.1:p.Ile788Val
NP_001393688.1:p.Ile788Val
NP_001393689.1:p.Ile788Val
NP_001393690.1:p.Ile745Val
NP_001393691.1:p.Ile745Val
NP_001393692.1:p.Ile743Val
NP_001393693.1:p.Ile745Val
NP_001393694.1:p.Ile743Val
NP_001393695.1:p.Ile692Val
NP_001393696.1:p.Ile692Val
NP_001393697.1:p.Ile700Val
NP_001393698.1:p.Ile656Val
NP_001393699.1:p.Ile692Val
NP_001393700.1:p.Ile642Val
NP_001393701.1:p.Ile656Val
NP_001393702.1:p.Ile642Val
NP_001393703.1:p.Ile613Val
NP_001393704.1:p.Ile546Val
NP_001393705.1:p.Ile546Val
NP_001393706.1:p.Ile546Val
NP_001393707.1:p.Ile546Val
NP_001393708.1:p.Ile489Val
NP_001393709.1:p.Ile489Val
NP_001393710.1:p.Ile489Val
NP_001393711.1:p.Ile489Val
NP_001393712.1:p.Ile446Val
NP_001393713.1:p.Ile458Val
NP_001393714.1:p.Ile449Val
NP_001393715.1:p.Ile446Val
NP_001393716.1:p.Ile444Val
NP_001393717.1:p.Ile393Val
NP_001393718.1:p.Ile393Val
NP_001393719.1:p.Ile393Val
NP_001393720.1:p.Ile353Val
NP_001393721.1:p.Ile305Val
NP_001393722.1:p.Ile305Val
NP_001393723.1:p.Ile305Val
NP_065680.1:p.Ile788Val
NP_065681.1:p.Ile788Val
NP_065681.1:p.Ile788Val
NP_065681.1:p.Ile788Val
NP_066124.1:p.Ile788Val
NP_066124.1:p.Ile788Val
LRG_518t1:c.2362A>G
LRG_518t2:c.2362A>G
LRG_518:g.46382A>G
LRG_518p1:p.Ile788Val
LRG_518p2:p.Ile788Val
NC_000010.10:g.43613898A>G
NM_001355216.1:c.1600A>G
NM_020630.4:c.2362A>G
NM_020630.6:c.2362A>G
NM_020975.4:c.2362A>G

Protein change:

I305V

Links:

dbSNP: rs1588876533

NCBI 1000 Genomes Browser:

rs1588876533

Molecular consequence:

NM_000323.2:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1600A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.2233A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.2233A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.2227A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.2233A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.2227A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.2074A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.2074A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.2098A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1966A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.2074A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1924A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1966A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1924A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1837A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1636A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1465A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1465A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1465A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1465A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1336A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1372A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1345A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1336A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1330A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.1177A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.1177A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.1177A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.1057A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.913A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.913A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.913A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2362A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Multiple endocrine neoplasia, type 2 (MEN2)
Identifiers:: MONDO: MONDO:0019003; MedGen: C4048306

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C1h11orf24 similar to human chromosome 11 open reading frame 24 [Rattus norvegic...
C1h11orf24 similar to human chromosome 11 open reading frame 24 [Rattus norvegicus]
Gene ID:309145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000939964	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 21, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004832206	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 11, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000939964

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 21, 2020)

germline

clinical testing

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

SCV004832206

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 11, 2024)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000939964.4

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

Description

This sequence change replaces isoleucine with valine at codon 788 of the RET protein (p.Ile788Val). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and valine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with RET-related conditions. This variant is not present in population databases (ExAC no frequency).

#	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 All of Us Research Program, National Institutes of Health, SCV004832206.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces isoleucine with valine at codon 788 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		2	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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