NM_020975.6(RET):c.2078G>A (p.Arg693His) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 19, 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:: RCV001232485.7

Allele description [Variation Report for NM_020975.6(RET):c.2078G>A (p.Arg693His)]

NM_020975.6(RET):c.2078G>A (p.Arg693His)

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.2078G>A (p.Arg693His)

HGVS:

NC_000010.11:g.43114678G>A
NG_007489.1:g.42610G>A
NM_000323.2:c.2078G>A
NM_001355216.2:c.1316G>A
NM_001406743.1:c.2078G>A
NM_001406744.1:c.2078G>A
NM_001406759.1:c.2078G>A
NM_001406760.1:c.2078G>A
NM_001406761.1:c.1949G>A
NM_001406762.1:c.1949G>A
NM_001406763.1:c.1943G>A
NM_001406764.1:c.1949G>A
NM_001406765.1:c.1943G>A
NM_001406766.1:c.1790G>A
NM_001406767.1:c.1790G>A
NM_001406768.1:c.1814G>A
NM_001406769.1:c.1682G>A
NM_001406770.1:c.1790G>A
NM_001406771.1:c.1640G>A
NM_001406772.1:c.1682G>A
NM_001406773.1:c.1640G>A
NM_001406774.1:c.1553G>A
NM_001406775.1:c.1352G>A
NM_001406776.1:c.1352G>A
NM_001406777.1:c.1352G>A
NM_001406778.1:c.1352G>A
NM_001406779.1:c.1181G>A
NM_001406780.1:c.1181G>A
NM_001406781.1:c.1181G>A
NM_001406782.1:c.1181G>A
NM_001406783.1:c.1052G>A
NM_001406784.1:c.1088G>A
NM_001406785.1:c.1061G>A
NM_001406786.1:c.1052G>A
NM_001406787.1:c.1046G>A
NM_001406788.1:c.893G>A
NM_001406789.1:c.893G>A
NM_001406790.1:c.893G>A
NM_001406791.1:c.773G>A
NM_001406792.1:c.629G>A
NM_001406793.1:c.629G>A
NM_001406794.1:c.629G>A
NM_020629.2:c.2078G>A
NM_020630.7:c.2078G>A
NM_020975.6:c.2078G>AMANE SELECT
NP_000314.1:p.Arg693His
NP_001342145.1:p.Arg439His
NP_001342145.1:p.Arg439His
NP_001393672.1:p.Arg693His
NP_001393673.1:p.Arg693His
NP_001393688.1:p.Arg693His
NP_001393689.1:p.Arg693His
NP_001393690.1:p.Arg650His
NP_001393691.1:p.Arg650His
NP_001393692.1:p.Arg648His
NP_001393693.1:p.Arg650His
NP_001393694.1:p.Arg648His
NP_001393695.1:p.Arg597His
NP_001393696.1:p.Arg597His
NP_001393697.1:p.Arg605His
NP_001393698.1:p.Arg561His
NP_001393699.1:p.Arg597His
NP_001393700.1:p.Arg547His
NP_001393701.1:p.Arg561His
NP_001393702.1:p.Arg547His
NP_001393703.1:p.Arg518His
NP_001393704.1:p.Arg451His
NP_001393705.1:p.Arg451His
NP_001393706.1:p.Arg451His
NP_001393707.1:p.Arg451His
NP_001393708.1:p.Arg394His
NP_001393709.1:p.Arg394His
NP_001393710.1:p.Arg394His
NP_001393711.1:p.Arg394His
NP_001393712.1:p.Arg351His
NP_001393713.1:p.Arg363His
NP_001393714.1:p.Arg354His
NP_001393715.1:p.Arg351His
NP_001393716.1:p.Arg349His
NP_001393717.1:p.Arg298His
NP_001393718.1:p.Arg298His
NP_001393719.1:p.Arg298His
NP_001393720.1:p.Arg258His
NP_001393721.1:p.Arg210His
NP_001393722.1:p.Arg210His
NP_001393723.1:p.Arg210His
NP_065680.1:p.Arg693His
NP_065681.1:p.Arg693His
NP_065681.1:p.Arg693His
NP_065681.1:p.Arg693His
NP_066124.1:p.Arg693His
NP_066124.1:p.Arg693His
LRG_518t1:c.2078G>A
LRG_518t2:c.2078G>A
LRG_518:g.42610G>A
LRG_518p1:p.Arg693His
LRG_518p2:p.Arg693His
NC_000010.10:g.43610126G>A
NM_001355216.1:c.1316G>A
NM_020630.4:c.2078G>A
NM_020630.6:c.2078G>A
NM_020975.4:c.2078G>A

Protein change:

R210H

Links:

dbSNP: rs1332256523

NCBI 1000 Genomes Browser:

rs1332256523

Molecular consequence:

NM_000323.2:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1316G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1949G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1949G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406763.1:c.1943G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1949G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406765.1:c.1943G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.1790G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.1790G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406768.1:c.1814G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.1790G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1640G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1682G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1640G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1553G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1352G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1181G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1181G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1181G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1181G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.1052G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1088G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.1061G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.1052G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406787.1:c.1046G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.893G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.893G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.893G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.773G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.629G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.629G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.629G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.2078G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.2078G>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
SCV001405047	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 19, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 25151137, 28492532
SCV004838650	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 17, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 32293499, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001405047

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 19, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004838650

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 17, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Detection of inherited mutations for hereditary cancer using target enrichment and next generation sequencing.

Guan Y, Hu H, Peng Y, Gong Y, Yi Y, Shao L, Liu T, Li G, Wang R, Dai P, Bignon YJ, Xiao Z, Yang L, Mu F, Xiao L, Xie Z, Yan W, Xu N, Zhou D, Yi X.

Fam Cancer. 2015 Mar;14(1):9-18. doi: 10.1007/s10689-014-9749-9.

PubMed [citation]

PMID:: 25151137

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

See all PubMed Citations (4)

Details of each submission

From Invitae, SCV001405047.5

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

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 693 of the RET protein (p.Arg693His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hereditary cancer (PMID: 25151137). ClinVar contains an entry for this variant (Variation ID: 959187). 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 disruptive. 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, SCV004838650.1

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

Description

This missense variant replaces arginine with histidine at codon 693 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). A functional study has reported that this variant increased oncogenic transformation properties of RET in mammalian cell models (PMID: 32293499). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer 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: May 1, 2024

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