NM_020975.6(RET):c.1998G>T (p.Lys666Asn) AND multiple conditions

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Aug 15, 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:: RCV003458339.1

Allele description [Variation Report for NM_020975.6(RET):c.1998G>T (p.Lys666Asn)]

NM_020975.6(RET):c.1998G>T (p.Lys666Asn)

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.1998G>T (p.Lys666Asn)

HGVS:

NC_000010.11:g.43114598G>T
NG_007489.1:g.42530G>T
NM_000323.2:c.1998G>T
NM_001355216.2:c.1236G>T
NM_001406743.1:c.1998G>T
NM_001406744.1:c.1998G>T
NM_001406759.1:c.1998G>T
NM_001406760.1:c.1998G>T
NM_001406761.1:c.1869G>T
NM_001406762.1:c.1869G>T
NM_001406764.1:c.1869G>T
NM_001406766.1:c.1710G>T
NM_001406767.1:c.1710G>T
NM_001406769.1:c.1602G>T
NM_001406770.1:c.1710G>T
NM_001406771.1:c.1560G>T
NM_001406772.1:c.1602G>T
NM_001406773.1:c.1560G>T
NM_001406774.1:c.1473G>T
NM_001406775.1:c.1272G>T
NM_001406776.1:c.1272G>T
NM_001406777.1:c.1272G>T
NM_001406778.1:c.1272G>T
NM_001406779.1:c.1101G>T
NM_001406780.1:c.1101G>T
NM_001406781.1:c.1101G>T
NM_001406782.1:c.1101G>T
NM_001406783.1:c.972G>T
NM_001406784.1:c.1008G>T
NM_001406785.1:c.981G>T
NM_001406786.1:c.972G>T
NM_001406788.1:c.813G>T
NM_001406789.1:c.813G>T
NM_001406790.1:c.813G>T
NM_001406791.1:c.693G>T
NM_001406792.1:c.549G>T
NM_001406793.1:c.549G>T
NM_001406794.1:c.549G>T
NM_020629.2:c.1998G>T
NM_020630.7:c.1998G>T
NM_020975.6:c.1998G>TMANE SELECT
NP_000314.1:p.Lys666Asn
NP_001342145.1:p.Lys412Asn
NP_001342145.1:p.Lys412Asn
NP_001393672.1:p.Lys666Asn
NP_001393673.1:p.Lys666Asn
NP_001393688.1:p.Lys666Asn
NP_001393689.1:p.Lys666Asn
NP_001393690.1:p.Lys623Asn
NP_001393691.1:p.Lys623Asn
NP_001393693.1:p.Lys623Asn
NP_001393695.1:p.Lys570Asn
NP_001393696.1:p.Lys570Asn
NP_001393698.1:p.Lys534Asn
NP_001393699.1:p.Lys570Asn
NP_001393700.1:p.Lys520Asn
NP_001393701.1:p.Lys534Asn
NP_001393702.1:p.Lys520Asn
NP_001393703.1:p.Lys491Asn
NP_001393704.1:p.Lys424Asn
NP_001393705.1:p.Lys424Asn
NP_001393706.1:p.Lys424Asn
NP_001393707.1:p.Lys424Asn
NP_001393708.1:p.Lys367Asn
NP_001393709.1:p.Lys367Asn
NP_001393710.1:p.Lys367Asn
NP_001393711.1:p.Lys367Asn
NP_001393712.1:p.Lys324Asn
NP_001393713.1:p.Lys336Asn
NP_001393714.1:p.Lys327Asn
NP_001393715.1:p.Lys324Asn
NP_001393717.1:p.Lys271Asn
NP_001393718.1:p.Lys271Asn
NP_001393719.1:p.Lys271Asn
NP_001393720.1:p.Lys231Asn
NP_001393721.1:p.Lys183Asn
NP_001393722.1:p.Lys183Asn
NP_001393723.1:p.Lys183Asn
NP_065680.1:p.Lys666Asn
NP_065681.1:p.Lys666Asn
NP_065681.1:p.Lys666Asn
NP_065681.1:p.Lys666Asn
NP_066124.1:p.Lys666Asn
NP_066124.1:p.Lys666Asn
NP_066124.1:p.Lys666Asn
LRG_518t1:c.1998G>T
LRG_518t2:c.1998G>T
LRG_518:g.42530G>T
LRG_518p1:p.Lys666Asn
LRG_518p2:p.Lys666Asn
NC_000010.10:g.43610046G>T
NM_001355216.1:c.1236G>T
NM_020630.4:c.1998G>T
NM_020630.5:c.1998G>T
NM_020630.6:c.1998G>T
NM_020975.4:c.1998G>T

Protein change:

K183N

Links:

dbSNP: rs146646971

NCBI 1000 Genomes Browser:

rs146646971

Molecular consequence:

NM_000323.2:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001355216.2:c.1236G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406743.1:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406744.1:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406759.1:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406760.1:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406761.1:c.1869G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406762.1:c.1869G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406764.1:c.1869G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406766.1:c.1710G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406767.1:c.1710G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406769.1:c.1602G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406770.1:c.1710G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406771.1:c.1560G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406772.1:c.1602G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406773.1:c.1560G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406774.1:c.1473G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406775.1:c.1272G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406776.1:c.1272G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406777.1:c.1272G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406778.1:c.1272G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406779.1:c.1101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406780.1:c.1101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406781.1:c.1101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406782.1:c.1101G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406783.1:c.972G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406784.1:c.1008G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406785.1:c.981G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406786.1:c.972G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406788.1:c.813G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406789.1:c.813G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406790.1:c.813G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406791.1:c.693G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406792.1:c.549G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406793.1:c.549G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001406794.1:c.549G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020629.2:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020630.7:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_020975.6:c.1998G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pheochromocytoma
Synonyms:: Chromaffinoma; Chromaffin paraganglioma; Chromaffin tumor; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0008233; MedGen: C0031511; Orphanet: 29072; OMIM: 171300; Human Phenotype Ontology: HP:0002666

Name:: Familial medullary thyroid carcinoma (MTC)
Synonyms:: Thyroid cancer, familial medullary; MTC, familial
Identifiers:: MONDO: MONDO:0007958; MedGen: C1833921; Orphanet: 653; OMIM: 155240

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004177183	Clinical Genomics Laboratory, Washington University in St. Louis	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Aug 15, 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

SCV004177183

Clinical Genomics Laboratory, Washington University in St. Louis

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Aug 15, 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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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 Clinical Genomics Laboratory, Washington University in St. Louis, SCV004177183.1

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

Description

The RET c.1998G>T (p.Lys666Asn) variant is reported in the literature in individuals and families affected with medullary thyroid carcinoma and pheochromocytoma as a low penetrance variant (Jaber T et al., PMID: 29408964; Lebeault M et al., PMID: 28946813; Muzza M et al., PMID: 20103606; Xu JY et al., PMID: 27673361). This variant has been reported in the ClinVar database as a germline pathogenic or likely pathogenic variant by 14 submitters. This variant is only observed on 7/282,120 alleles in the general population (gnomAD v.2.1.1), indicating it is not a common variant. Additionally, other amino acid substitutions at this codon (Arg, Asn, Glu, Met) have been reported in individuals with RET-related disorders and are considered pathogenic or likely pathogenic (Ahmed SA et al., PMID: 15858153., Borrello MG et al., PMID: 21690267; Lebeault M et al., PMID: 28946813, Mastroianno S et al., PMID: 21678021; Wells SA Jr et al., PMID: 25810047; Yamazaki M et al., PMID: 25319874). Computational predictors are uncertain as to the impact of this variant on RET function, but functional analyses of the p.Lys666Asn variant protein show increased kinase and transforming activity (Muzza M et al., PMID: 20103606). Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as likely pathogenic with low penetrance.

#	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: Jan 19, 2025

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