NM_020975.6(RET):c.1891G>A (p.Asp631Asn) AND Multiple endocrine neoplasia, type 2

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 6, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000696792.17

Allele description [Variation Report for NM_020975.6(RET):c.1891G>A (p.Asp631Asn)]

NM_020975.6(RET):c.1891G>A (p.Asp631Asn)

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.1891G>A (p.Asp631Asn)

HGVS:

NC_000010.11:g.43114491G>A
NG_007489.1:g.42423G>A
NM_000323.2:c.1891G>A
NM_001355216.2:c.1129G>A
NM_001406743.1:c.1891G>A
NM_001406744.1:c.1891G>A
NM_001406759.1:c.1891G>A
NM_001406760.1:c.1891G>A
NM_001406761.1:c.1762G>A
NM_001406762.1:c.1762G>A
NM_001406764.1:c.1762G>A
NM_001406766.1:c.1603G>A
NM_001406767.1:c.1603G>A
NM_001406769.1:c.1495G>A
NM_001406770.1:c.1603G>A
NM_001406771.1:c.1453G>A
NM_001406772.1:c.1495G>A
NM_001406773.1:c.1453G>A
NM_001406774.1:c.1366G>A
NM_001406775.1:c.1165G>A
NM_001406776.1:c.1165G>A
NM_001406777.1:c.1165G>A
NM_001406778.1:c.1165G>A
NM_001406779.1:c.994G>A
NM_001406780.1:c.994G>A
NM_001406781.1:c.994G>A
NM_001406782.1:c.994G>A
NM_001406783.1:c.865G>A
NM_001406784.1:c.901G>A
NM_001406785.1:c.874G>A
NM_001406786.1:c.865G>A
NM_001406788.1:c.706G>A
NM_001406789.1:c.706G>A
NM_001406790.1:c.706G>A
NM_001406791.1:c.586G>A
NM_001406792.1:c.442G>A
NM_001406793.1:c.442G>A
NM_001406794.1:c.442G>A
NM_020629.2:c.1891G>A
NM_020630.7:c.1891G>A
NM_020975.6:c.1891G>AMANE SELECT
NP_000314.1:p.Asp631Asn
NP_001342145.1:p.Asp377Asn
NP_001342145.1:p.Asp377Asn
NP_001393672.1:p.Asp631Asn
NP_001393673.1:p.Asp631Asn
NP_001393688.1:p.Asp631Asn
NP_001393689.1:p.Asp631Asn
NP_001393690.1:p.Asp588Asn
NP_001393691.1:p.Asp588Asn
NP_001393693.1:p.Asp588Asn
NP_001393695.1:p.Asp535Asn
NP_001393696.1:p.Asp535Asn
NP_001393698.1:p.Asp499Asn
NP_001393699.1:p.Asp535Asn
NP_001393700.1:p.Asp485Asn
NP_001393701.1:p.Asp499Asn
NP_001393702.1:p.Asp485Asn
NP_001393703.1:p.Asp456Asn
NP_001393704.1:p.Asp389Asn
NP_001393705.1:p.Asp389Asn
NP_001393706.1:p.Asp389Asn
NP_001393707.1:p.Asp389Asn
NP_001393708.1:p.Asp332Asn
NP_001393709.1:p.Asp332Asn
NP_001393710.1:p.Asp332Asn
NP_001393711.1:p.Asp332Asn
NP_001393712.1:p.Asp289Asn
NP_001393713.1:p.Asp301Asn
NP_001393714.1:p.Asp292Asn
NP_001393715.1:p.Asp289Asn
NP_001393717.1:p.Asp236Asn
NP_001393718.1:p.Asp236Asn
NP_001393719.1:p.Asp236Asn
NP_001393720.1:p.Asp196Asn
NP_001393721.1:p.Asp148Asn
NP_001393722.1:p.Asp148Asn
NP_001393723.1:p.Asp148Asn
NP_065680.1:p.Asp631Asn
NP_065681.1:p.Asp631Asn
NP_065681.1:p.Asp631Asn
NP_065681.1:p.Asp631Asn
NP_066124.1:p.Asp631Asn
NP_066124.1:p.Asp631Asn
LRG_518t1:c.1891G>A
LRG_518t2:c.1891G>A
LRG_518:g.42423G>A
LRG_518p1:p.Asp631Asn
LRG_518p2:p.Asp631Asn
NC_000010.10:g.43609939G>A
NM_001355216.1:c.1129G>A
NM_020630.4:c.1891G>A
NM_020630.5:c.1891G>A
NM_020630.6:c.1891G>A
NM_020975.4:c.1891G>A

Protein change:

D148N

Links:

dbSNP: rs377767406

NCBI 1000 Genomes Browser:

rs377767406

Molecular consequence:

NM_000323.2:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1129G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1762G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1762G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1762G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.1603G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.1603G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1495G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.1603G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1453G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1495G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1453G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1366G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1165G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1165G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1165G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1165G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.994G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.994G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.994G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.994G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.865G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.901G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.874G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.865G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.706G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.706G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.706G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.586G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.442G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.442G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.442G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.1891G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000825371	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 6, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16839264, 22274720, 10049754, 30927507, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000825371

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 6, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A rare extracellular D631Y germline mutation of the RET proto-oncogene in two Korean families with multiple endocrine neoplasia 2A.

Bae SJ, Kim DJ, Kim JY, Park SY, Choi SH, Song YD, Ki CS, Chung JH.

Thyroid. 2006 Jun;16(6):609-14.

PubMed [citation]

PMID:: 16839264

Patients with RET D631Y mutations most commonly present with pheochromocytoma and not medullary thyroid carcinoma.

Elston MS, Meyer-Rochow GY, Holdaway I, Conaglen JV.

Horm Metab Res. 2012 May;44(5):339-42. doi: 10.1055/s-0031-1295497. Epub 2012 Jan 24.

PubMed [citation]

PMID:: 22274720

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000825371.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

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. This variant disrupts the p.Asp631 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10049754, 16839264, 22274720). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 10049754). 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. ClinVar contains an entry for this variant (Variation ID: 24913). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 30927507). This variant is present in population databases (rs377767406, gnomAD 0.03%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 631 of the RET protein (p.Asp631Asn).

#	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

Last Updated: Nov 24, 2024

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