NM_020975.6(RET):c.701G>A (p.Arg234Gln) 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:: RCV000819920.10

Allele description [Variation Report for NM_020975.6(RET):c.701G>A (p.Arg234Gln)]

NM_020975.6(RET):c.701G>A (p.Arg234Gln)

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.701G>A (p.Arg234Gln)

HGVS:

NC_000010.11:g.43105027G>A
NG_007489.1:g.32959G>A
NM_000323.2:c.701G>A
NM_001355216.2:c.-62G>A
NM_001406743.1:c.701G>A
NM_001406744.1:c.701G>A
NM_001406759.1:c.701G>A
NM_001406760.1:c.701G>A
NM_001406761.1:c.572G>A
NM_001406762.1:c.572G>A
NM_001406763.1:c.701G>A
NM_001406764.1:c.572G>A
NM_001406765.1:c.701G>A
NM_001406766.1:c.413G>A
NM_001406767.1:c.413G>A
NM_001406768.1:c.572G>A
NM_001406769.1:c.701G>A
NM_001406770.1:c.413G>A
NM_001406772.1:c.701G>A
NM_001406774.1:c.572G>A
NM_020629.2:c.701G>A
NM_020630.7:c.701G>A
NM_020975.6:c.701G>AMANE SELECT
NP_000314.1:p.Arg234Gln
NP_001393672.1:p.Arg234Gln
NP_001393673.1:p.Arg234Gln
NP_001393688.1:p.Arg234Gln
NP_001393689.1:p.Arg234Gln
NP_001393690.1:p.Arg191Gln
NP_001393691.1:p.Arg191Gln
NP_001393692.1:p.Arg234Gln
NP_001393693.1:p.Arg191Gln
NP_001393694.1:p.Arg234Gln
NP_001393695.1:p.Arg138Gln
NP_001393696.1:p.Arg138Gln
NP_001393697.1:p.Arg191Gln
NP_001393698.1:p.Arg234Gln
NP_001393699.1:p.Arg138Gln
NP_001393701.1:p.Arg234Gln
NP_001393703.1:p.Arg191Gln
NP_065680.1:p.Arg234Gln
NP_065681.1:p.Arg234Gln
NP_065681.1:p.Arg234Gln
NP_065681.1:p.Arg234Gln
NP_066124.1:p.Arg234Gln
NP_066124.1:p.Arg234Gln
LRG_518t1:c.701G>A
LRG_518t2:c.701G>A
LRG_518:g.32959G>A
LRG_518p1:p.Arg234Gln
LRG_518p2:p.Arg234Gln
NC_000010.10:g.43600475G>A
NM_001355216.1:c.-62G>A
NM_020630.4:c.701G>A
NM_020630.6:c.701G>A
NM_020975.4:c.701G>A

Protein change:

R138Q

Links:

dbSNP: rs756216318

NCBI 1000 Genomes Browser:

rs756216318

Molecular consequence:

NM_000323.2:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.572G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.572G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.572G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.413G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.413G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.572G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.413G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.572G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.701G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.701G>A - 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
SCV000960607	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 5, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004830507	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

SCV000960607

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 5, 2024)

germline

clinical testing

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

SCV004830507

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	3	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):240-242.

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 Invitae, SCV000960607.7

#	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 arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 234 of the RET protein (p.Arg234Gln). 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: 662310). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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, SCV004830507.1

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

Description

This missense variant replaces arginine with glutamine at codon 234 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 been identified in 1/233328 chromosomes 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		3	not provided	not provided	not provided

Last Updated: May 1, 2024

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