VCV000216722.20 - ClinVar

NM_020975.6(RET):c.2931C>G (p.Ser977Arg)

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.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_020975.6(RET):c.2931C>G (p.Ser977Arg)

Variation ID: 216722 Accession: VCV000216722.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q11.21 10: 43123800 (GRCh38) [ NCBI UCSC ] 10: 43619248 (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	May 26, 2018	Oct 8, 2024	Apr 12, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_020975.6:c.2931C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_066124.1:p.Ser977Arg	missense
NM_000323.2:c.2931C>G	NP_000314.1:p.Ser977Arg	missense
NM_001355216.2:c.2169C>G	NP_001342145.1:p.Ser723Arg	missense
NM_001406743.1:c.2931C>G	NP_001393672.1:p.Ser977Arg	missense
NM_001406744.1:c.2931C>G	NP_001393673.1:p.Ser977Arg	missense
NM_001406759.1:c.2931C>G	NP_001393688.1:p.Ser977Arg	missense
NM_001406760.1:c.2931C>G	NP_001393689.1:p.Ser977Arg	missense
NM_001406761.1:c.2802C>G	NP_001393690.1:p.Ser934Arg	missense
NM_001406762.1:c.2802C>G	NP_001393691.1:p.Ser934Arg	missense
NM_001406763.1:c.2796C>G	NP_001393692.1:p.Ser932Arg	missense
NM_001406764.1:c.2802C>G	NP_001393693.1:p.Ser934Arg	missense
NM_001406765.1:c.2796C>G	NP_001393694.1:p.Ser932Arg	missense
NM_001406766.1:c.2643C>G	NP_001393695.1:p.Ser881Arg	missense
NM_001406767.1:c.2643C>G	NP_001393696.1:p.Ser881Arg	missense
NM_001406768.1:c.2667C>G	NP_001393697.1:p.Ser889Arg	missense
NM_001406769.1:c.2535C>G	NP_001393698.1:p.Ser845Arg	missense
NM_001406770.1:c.2643C>G	NP_001393699.1:p.Ser881Arg	missense
NM_001406771.1:c.2493C>G	NP_001393700.1:p.Ser831Arg	missense
NM_001406772.1:c.2535C>G	NP_001393701.1:p.Ser845Arg	missense
NM_001406773.1:c.2493C>G	NP_001393702.1:p.Ser831Arg	missense
NM_001406774.1:c.2406C>G	NP_001393703.1:p.Ser802Arg	missense
NM_001406775.1:c.2205C>G	NP_001393704.1:p.Ser735Arg	missense
NM_001406776.1:c.2205C>G	NP_001393705.1:p.Ser735Arg	missense
NM_001406777.1:c.2205C>G	NP_001393706.1:p.Ser735Arg	missense
NM_001406778.1:c.2205C>G	NP_001393707.1:p.Ser735Arg	missense
NM_001406779.1:c.2034C>G	NP_001393708.1:p.Ser678Arg	missense
NM_001406780.1:c.2034C>G	NP_001393709.1:p.Ser678Arg	missense
NM_001406781.1:c.2034C>G	NP_001393710.1:p.Ser678Arg	missense
NM_001406782.1:c.2034C>G	NP_001393711.1:p.Ser678Arg	missense
NM_001406783.1:c.1905C>G	NP_001393712.1:p.Ser635Arg	missense
NM_001406784.1:c.1941C>G	NP_001393713.1:p.Ser647Arg	missense
NM_001406785.1:c.1914C>G	NP_001393714.1:p.Ser638Arg	missense
NM_001406786.1:c.1905C>G	NP_001393715.1:p.Ser635Arg	missense
NM_001406787.1:c.1899C>G	NP_001393716.1:p.Ser633Arg	missense
NM_001406788.1:c.1746C>G	NP_001393717.1:p.Ser582Arg	missense
NM_001406789.1:c.1746C>G	NP_001393718.1:p.Ser582Arg	missense
NM_001406790.1:c.1746C>G	NP_001393719.1:p.Ser582Arg	missense
NM_001406791.1:c.1626C>G	NP_001393720.1:p.Ser542Arg	missense
NM_001406792.1:c.1482C>G	NP_001393721.1:p.Ser494Arg	missense
NM_001406793.1:c.1482C>G	NP_001393722.1:p.Ser494Arg	missense
NM_001406794.1:c.1482C>G	NP_001393723.1:p.Ser494Arg	missense
NM_020629.2:c.2931C>G	NP_065680.1:p.Ser977Arg	missense
NM_020630.7:c.2931C>G	NP_065681.1:p.Ser977Arg	missense
NC_000010.11:g.43123800C>G
NC_000010.10:g.43619248C>G
NG_007489.1:g.51732C>G
LRG_518:g.51732C>G
LRG_518t1:c.2931C>G	LRG_518p1:p.Ser977Arg
LRG_518t2:c.2931C>G	LRG_518p2:p.Ser977Arg

... more HGVS ... less HGVS

Protein change

S977R, S723R, S635R, S647R, S845R, S889R, S542R, S735R, S831R, S881R, S494R, S582R, S638R, S678R, S934R, S633R, S802R, S932R

Other names

Canonical SPDI

NC_000010.11:43123799:C:G

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) 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA041466 dbSNP: rs375414982 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.
Multiple endocrine neoplasia, type 2	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 27, 2024	RCV000198200.11
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Feb 11, 2024	RCV000679738.8
Hereditary cancer-predisposing syndrome	Uncertain significance (1)	criteria provided, single submitter	Apr 12, 2024	RCV001017530.6
Multiple endocrine neoplasia type 2A	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jul 2, 2018	RCV000662775.4
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	Jan 18, 2022	RCV002492921.1
Hirschsprung disease, susceptibility to, 1	Uncertain significance (1)	criteria provided, single submitter	Mar 20, 2024	RCV003462337.2

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 (Jan 27, 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: SCV000255051.8 First in ClinVar: Oct 11, 2015 Last updated: Feb 20, 2024	Comment: This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 977 of the RET protein (p.Ser977Arg). … (more) This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 977 of the RET protein (p.Ser977Arg). This variant is present in population databases (rs375414982, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216722). 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. (less)
Uncertain significance (Jan 18, 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: SCV002797545.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Uncertain significance (Sep 22, 2017)	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: SCV000785576.2 First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018	Publications: PubMed (1) PubMed: 25877891
Uncertain significance (Oct 05, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000807038.1 First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018
Uncertain significance (Jul 02, 2018)	criteria provided, single submitter (Mendelics Assertion Criteria 2017) Method: clinical testing	Multiple endocrine neoplasia, type 2a Affected status: unknown Allele origin: unknown	Mendelics Accession: SCV000838407.2 First in ClinVar: Oct 10, 2018 Last updated: Dec 11, 2022
Uncertain significance (Feb 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV003195174.2 First in ClinVar: Feb 07, 2023 Last updated: Oct 08, 2024	Comment: In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to … (more) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25877891, 14633923) (less)
Uncertain Significance (Jan 08, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Multiple endocrine neoplasia, type 2 (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004838701.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Comment: This missense variant replaces serine with arginine at codon 977 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on … (more) This missense variant replaces serine with arginine at codon 977 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/251384 chromosomes 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. (less) Number of individuals with the variant: 14
Uncertain significance (Mar 20, 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: SCV004206728.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (Apr 12, 2024)	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: SCV001178620.6 First in ClinVar: Mar 16, 2020 Last updated: Aug 11, 2024	Comment: The p.S977R variant (also known as c.2931C>G), located in coding exon 17 of the RET gene, results from a C to G substitution at nucleotide … (more) The p.S977R variant (also known as c.2931C>G), located in coding exon 17 of the RET gene, results from a C to G substitution at nucleotide position 2931. The serine at codon 977 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a multiple endocrine neoplasia type 2 (MEN2) disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This variant has been detected in multiple individuals with no reported features of RET-associated disease (Ambry internal data). Based on the supporting evidence, the association of this alteration with Hirschprung disease is unknown; however, the association of this alteration with MEN2 is unlikely. (less)

Comment:

This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 977 of the RET protein (p.Ser977Arg). This variant is present in population databases (rs375414982, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216722). 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.

Comment:

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 25877891, 14633923)

Comment:

This missense variant replaces serine with arginine at codon 977 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 7/251384 chromosomes 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.

Comment:

The p.S977R variant (also known as c.2931C>G), located in coding exon 17 of the RET gene, results from a C to G substitution at nucleotide position 2931. The serine at codon 977 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a multiple endocrine neoplasia type 2 (MEN2) disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). This variant has been detected in multiple individuals with no reported features of RET-associated disease (Ambry internal data). Based on the supporting evidence, the association of this alteration with Hirschprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.

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
Personalized genomic analyses for cancer mutation discovery and interpretation.	Jones S	Science translational medicine	2015	PMID: 25877891

Text-mined citations for rs375414982 ...

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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_020975.6(RET):c.2931C>G (p.Ser977Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs375414982 ...