VCV000024943.19 - ClinVar

NM_020975.6(RET):c.2452G>A (p.Glu818Lys)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(7); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020975.6(RET):c.2452G>A (p.Glu818Lys)

Variation ID: 24943 Accession: VCV000024943.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43119590 (GRCh38) [ NCBI UCSC ] 10: 43615038 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2014	Jun 17, 2024	Mar 9, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.2452G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Glu818Lys	missense
NM_000323.2:c.2452G>A	NP_000314.1:p.Glu818Lys	missense
NM_001355216.2:c.1690G>A	NP_001342145.1:p.Glu564Lys	missense
NM_001406743.1:c.2452G>A	NP_001393672.1:p.Glu818Lys	missense
NM_001406744.1:c.2452G>A	NP_001393673.1:p.Glu818Lys	missense
NM_001406759.1:c.2452G>A	NP_001393688.1:p.Glu818Lys	missense
NM_001406760.1:c.2452G>A	NP_001393689.1:p.Glu818Lys	missense
NM_001406761.1:c.2323G>A	NP_001393690.1:p.Glu775Lys	missense
NM_001406762.1:c.2323G>A	NP_001393691.1:p.Glu775Lys	missense
NM_001406763.1:c.2317G>A	NP_001393692.1:p.Glu773Lys	missense
NM_001406764.1:c.2323G>A	NP_001393693.1:p.Glu775Lys	missense
NM_001406765.1:c.2317G>A	NP_001393694.1:p.Glu773Lys	missense
NM_001406766.1:c.2164G>A	NP_001393695.1:p.Glu722Lys	missense
NM_001406767.1:c.2164G>A	NP_001393696.1:p.Glu722Lys	missense
NM_001406768.1:c.2188G>A	NP_001393697.1:p.Glu730Lys	missense
NM_001406769.1:c.2056G>A	NP_001393698.1:p.Glu686Lys	missense
NM_001406770.1:c.2164G>A	NP_001393699.1:p.Glu722Lys	missense
NM_001406771.1:c.2014G>A	NP_001393700.1:p.Glu672Lys	missense
NM_001406772.1:c.2056G>A	NP_001393701.1:p.Glu686Lys	missense
NM_001406773.1:c.2014G>A	NP_001393702.1:p.Glu672Lys	missense
NM_001406774.1:c.1927G>A	NP_001393703.1:p.Glu643Lys	missense
NM_001406775.1:c.1726G>A	NP_001393704.1:p.Glu576Lys	missense
NM_001406776.1:c.1726G>A	NP_001393705.1:p.Glu576Lys	missense
NM_001406777.1:c.1726G>A	NP_001393706.1:p.Glu576Lys	missense
NM_001406778.1:c.1726G>A	NP_001393707.1:p.Glu576Lys	missense
NM_001406779.1:c.1555G>A	NP_001393708.1:p.Glu519Lys	missense
NM_001406780.1:c.1555G>A	NP_001393709.1:p.Glu519Lys	missense
NM_001406781.1:c.1555G>A	NP_001393710.1:p.Glu519Lys	missense
NM_001406782.1:c.1555G>A	NP_001393711.1:p.Glu519Lys	missense
NM_001406783.1:c.1426G>A	NP_001393712.1:p.Glu476Lys	missense
NM_001406784.1:c.1462G>A	NP_001393713.1:p.Glu488Lys	missense
NM_001406785.1:c.1435G>A	NP_001393714.1:p.Glu479Lys	missense
NM_001406786.1:c.1426G>A	NP_001393715.1:p.Glu476Lys	missense
NM_001406787.1:c.1420G>A	NP_001393716.1:p.Glu474Lys	missense
NM_001406788.1:c.1267G>A	NP_001393717.1:p.Glu423Lys	missense
NM_001406789.1:c.1267G>A	NP_001393718.1:p.Glu423Lys	missense
NM_001406790.1:c.1267G>A	NP_001393719.1:p.Glu423Lys	missense
NM_001406791.1:c.1147G>A	NP_001393720.1:p.Glu383Lys	missense
NM_001406792.1:c.1003G>A	NP_001393721.1:p.Glu335Lys	missense
NM_001406793.1:c.1003G>A	NP_001393722.1:p.Glu335Lys	missense
NM_001406794.1:c.1003G>A	NP_001393723.1:p.Glu335Lys	missense
NM_020629.2:c.2452G>A	NP_065680.1:p.Glu818Lys	missense
NM_020630.7:c.2452G>A	NP_065681.1:p.Glu818Lys	missense
NC_000010.11:g.43119590G>A
NC_000010.10:g.43615038G>A
NG_007489.1:g.47522G>A
LRG_518:g.47522G>A
LRG_518t1:c.2452G>A	LRG_518p1:p.Glu818Lys
LRG_518t2:c.2452G>A	LRG_518p2:p.Glu818Lys

... more HGVS ... less HGVS

Protein change

E564K, E383K, E476K, E773K, E479K, E519K, E576K, E672K, E686K, E730K, E423K, E474K, E488K, E722K, E335K, E643K, E775K

Other names

Canonical SPDI

NC_000010.11:43119589:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA008797 dbSNP: rs377767420 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
RET		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	3595	3717

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Medullary thyroid carcinoma	Uncertain significance (1)	no assertion criteria provided	Jun 1, 2014	RCV000148782.11
Multiple endocrine neoplasia type 2B	Uncertain significance (1)	criteria provided, single submitter	Dec 8, 2015	RCV000410539.10
Multiple endocrine neoplasia type 2A	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 18, 2023	RCV000411157.11
Multiple endocrine neoplasia, type 2	Uncertain significance (1)	criteria provided, single submitter	Jan 14, 2024	RCV000799360.16
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Sep 2, 2022	RCV000571277.14
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Mar 9, 2024	RCV003460490.2
Familial medullary thyroid carcinoma Hirschsprung disease, susceptibility to, 1 Multiple endocrine neoplasia type 2A Multiple endocrine neoplasia type 2B Pheochromocytoma	Uncertain significance (1)	criteria provided, single submitter	Aug 25, 2021	RCV002490401.8

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Aug 17, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002529978.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The RET c.2452G>A (p.E818K) variant has been reported in at least two individuals with medullary thyroid carcinoma with or without primary hyperparathyroidism or phaeochromocytoma (PMID:18058472, … (more) The RET c.2452G>A (p.E818K) variant has been reported in at least two individuals with medullary thyroid carcinoma with or without primary hyperparathyroidism or phaeochromocytoma (PMID:18058472, 33340421). It was observed in 5/34364 chromosomes of the Latino subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 24943). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (2) PubMed: 18058472‚ 33340421
Uncertain significance (Dec 08, 2015)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489754.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 21479187‚ 25637381‚ 18058472
Uncertain significance (Dec 08, 2015)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Multiple endocrine neoplasia type 2B Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000489753.2 First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022	Publications: PubMed (3) PubMed: 21479187‚ 25637381‚ 18058472
Uncertain significance (Aug 25, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Familial medullary thyroid carcinoma Multiple endocrine neoplasia type 2B Pheochromocytoma Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002788824.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Apr 18, 2023)	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV004018475.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Comment: This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Uncertain significance (Jan 14, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Multiple endocrine neoplasia, type 2 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000939019.6 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 18058472 Comment: This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 818 of the RET protein … (more) This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 818 of the RET protein (p.Glu818Lys). This variant is present in population databases (rs377767420, gnomAD 0.01%). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 18058472). ClinVar contains an entry for this variant (Variation ID: 24943). 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. (less)
Likely benign (Sep 02, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000674842.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 18058472‚ 21479187‚ 25637381‚ 33340421 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Mar 09, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004208696.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Jun 01, 2014)	no assertion criteria provided Method: research	Thyroid carcinoma, medullary (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	CSER _CC_NCGL, University of Washington Study: ESP 6500 variant annotation Accession: SCV000190520.1 First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 Comment: Variants classified for the Actionable exomic incidental findings in 6503 participants: challenges of variant classification manuscript

Comment:

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 818 of the RET protein (p.Glu818Lys). This variant is present in population databases (rs377767420, gnomAD 0.01%). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 18058472). ClinVar contains an entry for this variant (Variation ID: 24943). 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.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Diagnostic RET genetic testing in 1,058 index patients: A UK centre perspective.	Fussey JM	Clinical endocrinology	2021	PMID: 33340421
Actionable exomic incidental findings in 6503 participants: challenges of variant classification.	Amendola LM	Genome research	2015	PMID: 25637381
Predicting phenotypic severity of uncertain gene variants in the RET proto-oncogene.	Crockett DK	PloS one	2011	PMID: 21479187
The occurrence and the type of germline mutations in the RET gene in patients with medullary thyroid carcinoma and their unaffected kindred's from Central Poland.	Paszko Z	Cancer investigation	2007	PMID: 18058472

Text-mined citations for rs377767420 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.2452G>A (p.Glu818Lys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377767420 ...