NM_020975.6(RET):c.266A>G (p.Gln89Arg) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 24, 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:: RCV000691693.9

Allele description [Variation Report for NM_020975.6(RET):c.266A>G (p.Gln89Arg)]

NM_020975.6(RET):c.266A>G (p.Gln89Arg)

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.266A>G (p.Gln89Arg)

HGVS:

NC_000010.11:g.43100651A>G
NG_007489.1:g.28583A>G
NM_000323.2:c.266A>G
NM_001406743.1:c.266A>G
NM_001406744.1:c.266A>G
NM_001406759.1:c.266A>G
NM_001406760.1:c.266A>G
NM_001406761.1:c.266A>G
NM_001406762.1:c.266A>G
NM_001406763.1:c.266A>G
NM_001406764.1:c.266A>G
NM_001406765.1:c.266A>G
NM_001406766.1:c.266A>G
NM_001406767.1:c.266A>G
NM_001406768.1:c.266A>G
NM_001406769.1:c.266A>G
NM_001406770.1:c.266A>G
NM_001406771.1:c.266A>G
NM_001406772.1:c.266A>G
NM_001406773.1:c.266A>G
NM_001406774.1:c.266A>G
NM_001406775.1:c.266A>G
NM_001406776.1:c.266A>G
NM_001406777.1:c.266A>G
NM_001406778.1:c.266A>G
NM_001406779.1:c.266A>G
NM_001406780.1:c.266A>G
NM_001406781.1:c.266A>G
NM_001406782.1:c.266A>G
NM_001406783.1:c.266A>G
NM_001406785.1:c.266A>G
NM_001406786.1:c.266A>G
NM_001406787.1:c.266A>G
NM_001406788.1:c.266A>G
NM_001406789.1:c.266A>G
NM_001406790.1:c.266A>G
NM_001406791.1:c.266A>G
NM_020629.2:c.266A>G
NM_020630.7:c.266A>G
NM_020975.6:c.266A>GMANE SELECT
NP_000314.1:p.Gln89Arg
NP_001393672.1:p.Gln89Arg
NP_001393673.1:p.Gln89Arg
NP_001393688.1:p.Gln89Arg
NP_001393689.1:p.Gln89Arg
NP_001393690.1:p.Gln89Arg
NP_001393691.1:p.Gln89Arg
NP_001393692.1:p.Gln89Arg
NP_001393693.1:p.Gln89Arg
NP_001393694.1:p.Gln89Arg
NP_001393695.1:p.Gln89Arg
NP_001393696.1:p.Gln89Arg
NP_001393697.1:p.Gln89Arg
NP_001393698.1:p.Gln89Arg
NP_001393699.1:p.Gln89Arg
NP_001393700.1:p.Gln89Arg
NP_001393701.1:p.Gln89Arg
NP_001393702.1:p.Gln89Arg
NP_001393703.1:p.Gln89Arg
NP_001393704.1:p.Gln89Arg
NP_001393705.1:p.Gln89Arg
NP_001393706.1:p.Gln89Arg
NP_001393707.1:p.Gln89Arg
NP_001393708.1:p.Gln89Arg
NP_001393709.1:p.Gln89Arg
NP_001393710.1:p.Gln89Arg
NP_001393711.1:p.Gln89Arg
NP_001393712.1:p.Gln89Arg
NP_001393714.1:p.Gln89Arg
NP_001393715.1:p.Gln89Arg
NP_001393716.1:p.Gln89Arg
NP_001393717.1:p.Gln89Arg
NP_001393718.1:p.Gln89Arg
NP_001393719.1:p.Gln89Arg
NP_001393720.1:p.Gln89Arg
NP_065680.1:p.Gln89Arg
NP_065681.1:p.Gln89Arg
NP_065681.1:p.Gln89Arg
NP_065681.1:p.Gln89Arg
NP_066124.1:p.Gln89Arg
NP_066124.1:p.Gln89Arg
LRG_518t1:c.266A>G
LRG_518t2:c.266A>G
LRG_518:g.28583A>G
LRG_518p1:p.Gln89Arg
LRG_518p2:p.Gln89Arg
NC_000010.10:g.43596099A>G
NM_020630.4:c.266A>G
NM_020630.6:c.266A>G
NM_020975.4:c.266A>G

Protein change:

Q89R

Links:

dbSNP: rs1564489449

NCBI 1000 Genomes Browser:

rs1564489449

Molecular consequence:

NM_000323.2:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.266A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.266A>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000819482	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Sep 24, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004827743	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jun 8, 2023)	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

SCV000819482

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Sep 24, 2023)

germline

clinical testing

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

SCV004827743

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jun 8, 2023)

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	1	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, SCV000819482.4

#	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 glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 89 of the RET protein (p.Gln89Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 570756). 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. 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.

#	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, SCV004827743.1

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

Description

This missense variant replaces glutamine with arginine at codon 89 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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