VCV000024913.22 - ClinVar

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

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.

(8)

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(6); Likely benign(2)

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.1891G>A (p.Asp631Asn)

Variation ID: 24913 Accession: VCV000024913.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43114491 (GRCh38) [ NCBI UCSC ] 10: 43609939 (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 19, 2017	Nov 24, 2024	Aug 9, 2024

HGVS

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

... more HGVS ... less HGVS

Protein change

D631N, D377N, D332N, D389N, D499N, D301N, D289N, D485N, D535N, D588N, D148N, D196N, D236N, D292N, D456N

Other names

Canonical SPDI

NC_000010.11:43114490: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.

The Genome Aggregation Database (gnomAD) 0.00004

Trans-Omics for Precision Medicine (TOPMed) 0.00004

Exome Aggregation Consortium (ExAC) 0.00006

Links

ClinGen: CA008190 dbSNP: rs377767406 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	3598	3720

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.
Hereditary cancer-predisposing syndrome	Likely benign (1)	criteria provided, single submitter	Nov 29, 2021	RCV000564566.11
Multiple endocrine neoplasia, type 2	Uncertain significance (1)	criteria provided, single submitter	Aug 6, 2023	RCV000696792.17
not provided	Uncertain significance (1)	criteria provided, single submitter	Jan 3, 2024	RCV000519407.10
not specified	Uncertain significance (1)	criteria provided, single submitter	Sep 25, 2019	RCV001818172.11
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	Apr 27, 2022	RCV002477000.8
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Jun 22, 2023	RCV003460488.1
Multiple endocrine neoplasia type 2A	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Aug 9, 2024	RCV004786279.1

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 (Apr 27, 2022)	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: SCV000896058.2 First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Jun 22, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hirschsprung disease, susceptibility to, 1 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004206713.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Uncertain significance (Aug 06, 2023)	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: SCV000825371.7 First in ClinVar: Oct 10, 2018 Last updated: Feb 28, 2024	Publications: PubMed (5) PubMed: 28492532‚ 10049754‚ 16839264‚ 22274720‚ 30927507 Comment: 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 … (more) 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). (less)
Uncertain significance (Jan 03, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000618423.3 First in ClinVar: Dec 19, 2017 Last updated: Sep 29, 2024	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate absent transforming activity and no independent dimerization (PMID: … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate absent transforming activity and no independent dimerization (PMID: 10049754); This variant is associated with the following publications: (PMID: 23264394, 26639839, 21479187, 25810047, 14633923, 10049754, 30927507, 35534704) (less)
Uncertain significance (Sep 25, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002071196.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Nov 29, 2021)	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: SCV000674829.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 10049754‚ 25810047‚ 30927507 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 15, 2024)	criteria provided, single submitter (St. Jude Assertion Criteria 2020) Method: clinical testing	Multiple endocrine neoplasia type 2A Affected status: unknown Allele origin: germline	St. Jude Molecular Pathology, St. Jude Children's Research Hospital Accession: SCV005402301.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: The RET c.1891G>A (p.Asp631Asn) missense change has a maximum subpopulation frequency of 0.04% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about … (more) The RET c.1891G>A (p.Asp631Asn) missense change has a maximum subpopulation frequency of 0.04% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in the literature in an individual with medullary thyroid cancer (PMID: 30927507). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. (less)
Likely benign (Aug 09, 2024)	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: SCV005403696.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Comment: This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease … (more) This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)

Comment:

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).

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate absent transforming activity and no independent dimerization (PMID: 10049754); This variant is associated with the following publications: (PMID: 23264394, 26639839, 21479187, 25810047, 14633923, 10049754, 30927507, 35534704)

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.

Comment:

The RET c.1891G>A (p.Asp631Asn) missense change has a maximum subpopulation frequency of 0.04% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. This variant has been reported in the literature in an individual with medullary thyroid cancer (PMID: 30927507). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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
p.Ser891Ala RET gene mutations in medullary thyroid cancer: Phenotypical and genealogical characterization of 28 apparently unrelated kindreds and founder effect uncovering in Northern Italy.	Giacché M	Human mutation	2019	PMID: 30927507
Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma.	Wells SA Jr	Thyroid : official journal of the American Thyroid Association	2015	PMID: 25810047
Patients with RET D631Y mutations most commonly present with pheochromocytoma and not medullary thyroid carcinoma.	Elston MS	Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme	2012	PMID: 22274720
A rare extracellular D631Y germline mutation of the RET proto-oncogene in two Korean families with multiple endocrine neoplasia 2A.	Bae SJ	Thyroid : official journal of the American Thyroid Association	2006	PMID: 16839264
Mechanism of Ret activation by a mutation at aspartic acid 631 identified in sporadic pheochromocytoma.	Asai N	Biochemical and biophysical research communications	1999	PMID: 10049754

Text-mined citations for rs377767406 ...

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 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377767406 ...