ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.785T>C (p.Val262Ala)
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.
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(8); Likely benign(8)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_020975.6(RET):c.785T>C (p.Val262Ala)
Variation ID: 41845 Accession: VCV000041845.44
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.21 10: 43105111 (GRCh38) [ NCBI UCSC ] 10: 43600559 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Apr 12, 2013 May 12, 2024 Apr 9, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_020975.6:c.785T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Val262Ala missense NM_000323.2:c.785T>C NP_000314.1:p.Val262Ala missense NM_001355216.2:c.23T>C NP_001342145.1:p.Val8Ala missense NM_001406743.1:c.785T>C NP_001393672.1:p.Val262Ala missense NM_001406744.1:c.785T>C NP_001393673.1:p.Val262Ala missense NM_001406759.1:c.785T>C NP_001393688.1:p.Val262Ala missense NM_001406760.1:c.785T>C NP_001393689.1:p.Val262Ala missense NM_001406761.1:c.656T>C NP_001393690.1:p.Val219Ala missense NM_001406762.1:c.656T>C NP_001393691.1:p.Val219Ala missense NM_001406763.1:c.785T>C NP_001393692.1:p.Val262Ala missense NM_001406764.1:c.656T>C NP_001393693.1:p.Val219Ala missense NM_001406765.1:c.785T>C NP_001393694.1:p.Val262Ala missense NM_001406766.1:c.497T>C NP_001393695.1:p.Val166Ala missense NM_001406767.1:c.497T>C NP_001393696.1:p.Val166Ala missense NM_001406768.1:c.656T>C NP_001393697.1:p.Val219Ala missense NM_001406769.1:c.785T>C NP_001393698.1:p.Val262Ala missense NM_001406770.1:c.497T>C NP_001393699.1:p.Val166Ala missense NM_001406772.1:c.785T>C NP_001393701.1:p.Val262Ala missense NM_001406774.1:c.656T>C NP_001393703.1:p.Val219Ala missense NM_020629.2:c.785T>C NP_065680.1:p.Val262Ala missense NM_020630.7:c.785T>C NP_065681.1:p.Val262Ala missense NC_000010.11:g.43105111T>C NC_000010.10:g.43600559T>C NG_007489.1:g.33043T>C LRG_518:g.33043T>C LRG_518t1:c.785T>C LRG_518p1:p.Val262Ala LRG_518t2:c.785T>C LRG_518p2:p.Val262Ala - Protein change
- V262A, V8A, V219A, V166A
- Other names
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- Canonical SPDI
- NC_000010.11:43105110:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe 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.
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0.00020 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD) 0.00024
Exome Aggregation Consortium (ExAC) 0.00025
The Genome Aggregation Database (gnomAD), exomes 0.00025
Trans-Omics for Precision Medicine (TOPMed) 0.00025
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 | ||
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HI score
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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. |
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RET | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
3522 | 3642 |
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. |
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Likely benign (4) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000034777.24 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 25, 2024 | RCV000123327.15 | |
Uncertain significance (1) |
no assertion criteria provided
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Jun 1, 2014 | RCV000148775.5 | |
Uncertain significance (2) |
criteria provided, multiple submitters, no conflicts
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May 4, 2020 | RCV000223157.11 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Jan 3, 2022 | RCV000573525.10 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Apr 9, 2024 | RCV000663296.9 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 27, 2019 | RCV001103897.6 | |
Likely benign (1) |
criteria provided, single submitter
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Nov 27, 2019 | RCV001104177.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 27, 2019 | RCV001103898.6 | |
Uncertain significance (1) |
criteria provided, single submitter
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Nov 27, 2019 | RCV001103896.6 | |
Uncertain significance (1) |
no assertion criteria provided
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- | RCV001269367.3 | |
Likely benign (1) |
criteria provided, single submitter
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Jan 31, 2023 | RCV004528165.1 | |
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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. |
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Uncertain significance
(May 04, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: no
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV002068400.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
Comment:
DNA sequence analysis of the RET gene demonstrated a sequence change, c.785T>C, in exon 4 that results in an amino acid change, p.Val262Ala. This sequence … (more)
DNA sequence analysis of the RET gene demonstrated a sequence change, c.785T>C, in exon 4 that results in an amino acid change, p.Val262Ala. This sequence change has been described in the gnomAD database with a frequency of 0.043% in the South Asian sub-population (dbSNP rs139790943). The p.Val262Ala change has been reported in an individual with Hirshsprung's disease (PMID: 11955539). The p.Val262Ala change affects a moderately conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Val262Ala substitution appears to be deleterious based on in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Val262Ala change remains unknown at this time. (less)
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Uncertain significance
(Jan 03, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002527924.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
To the best of our knowledge, the RET c.785T>C (p.V262A) variant has not been reported in individuals with RET-related disease. It was observed in 69/277836 … (more)
To the best of our knowledge, the RET c.785T>C (p.V262A) variant has not been reported in individuals with RET-related disease. It was observed in 69/277836 chromosomes across the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 41845). In silico tools suggest the impact of the variant on protein function is deleterious, though these predictions have not been confirmed by functional studies. 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)
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Likely benign
(Mar 30, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000279597.11
First in ClinVar: May 29, 2016 Last updated: Mar 04, 2023 |
Comment:
This variant is associated with the following publications: (PMID: 25637381, 24336963, 11955539, 20956458, 22703879, 24055113, 15956201, 27884173, 31159747, 31614935)
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Uncertain significance
(Jan 24, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000540171.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more)
Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 4 papers, with comments suggesting VUS. It has been seen in unaffected patients, as well as one with Hirschprung's disease and an individual with pituitary adenomas but did not segregate in this family. This variant has a Max MAF of 0.032% in ExAC. It is classified with 2 stars as VUS by GeneDx, Invitae, Biesecker, and CSER_CC_NCGL. (less)
Method: Genome/Exome Filtration
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Uncertain significance
(Aug 01, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: yes
Allele origin:
germline
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GeneKor MSA
Accession: SCV000822200.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
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Likely benign
(Jun 11, 2018)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000664464.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
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)
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Likely benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002062909.13
First in ClinVar: Jan 29, 2022 Last updated: May 12, 2024 |
Comment:
RET: BS2
Number of individuals with the variant: 4
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Likely benign
(May 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000786544.2
First in ClinVar: Jul 15, 2018 Last updated: Jul 15, 2018 |
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Uncertain significance
(Dec 30, 2017)
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criteria provided, single submitter
Method: curation
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Multiple endocrine neoplasia type 2A
Affected status: yes
Allele origin:
unknown
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Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University
Accession: SCV000891636.1
First in ClinVar: Oct 10, 2018 Last updated: Oct 10, 2018 |
Geographic origin: Middle East
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Likely benign
(Nov 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Pheochromocytoma
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001260710.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Nov 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001260709.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
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Uncertain significance
(Nov 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Renal hypodysplasia/aplasia 1
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV001260711.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
|
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Likely benign
(Nov 27, 2019)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV001261020.1
First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Uncertain significance
(Jan 25, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000166634.14
First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024 |
Comment:
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 262 of the RET protein (p.Val262Ala). … (more)
This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 262 of the RET protein (p.Val262Ala). This variant is present in population databases (rs139790943, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with non-medullary thyroid carcinoma and Hirschsprung disease (PMID: 11955539, 31614935). ClinVar contains an entry for this variant (Variation ID: 41845). 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)
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Likely benign
(Jan 31, 2023)
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criteria provided, single submitter
Method: clinical testing
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RET-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV000807060.2
First in ClinVar: Apr 12, 2013 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Apr 09, 2024)
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criteria provided, single submitter
Method: clinical testing
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Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
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Mendelics
Accession: SCV000838371.3
First in ClinVar: Oct 10, 2018 Last updated: Apr 15, 2024 |
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variant of unknown significance
(Jul 13, 2012)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043470.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Uncertain significance.
Number of individuals with the variant: 1
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Uncertain significance
(-)
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no assertion criteria provided
Method: clinical testing
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Breast Cancer
Affected status: yes
Allele origin:
germline
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Center of Medical Genetics and Primary Health Care
Accession: SCV001448706.1
First in ClinVar: Dec 07, 2020 Last updated: Dec 07, 2020 |
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Uncertain significance
(Jun 01, 2014)
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no assertion criteria provided
Method: research
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Hirschsprung disease
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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CSER _CC_NCGL, University of Washington
Study: ESP 6500 variant annotation
Accession: SCV000190512.1 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
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Uncertain significance
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: no
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000920669.1
First in ClinVar: Jun 09, 2019 Last updated: Jun 09, 2019 |
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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. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Whole Genome Sequencing of Familial Non-Medullary Thyroid Cancer Identifies Germline Alterations in MAPK/ERK and PI3K/AKT Signaling Pathways. | Srivastava A | Biomolecules | 2019 | PMID: 31614935 |
Revisiting the morbid genome of Mendelian disorders. | Abouelhoda M | Genome biology | 2016 | PMID: 27884173 |
Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
Actionable, pathogenic incidental findings in 1,000 participants' exomes. | Dorschner MO | American journal of human genetics | 2013 | PMID: 24055113 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
No evidence of RET germline mutations in familial pituitary adenoma. | Heliövaara E | Journal of molecular endocrinology | 2010 | PMID: 20956458 |
Association between c135G/A genotype and RET proto-oncogene germline mutations and phenotype of Hirschsprung's disease. | Fitze G | Lancet (London, England) | 2002 | PMID: 11955539 |
Text-mined citations for rs139790943 ...
HelpRecord last updated May 12, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.