ClinVar Genomic variation as it relates to human health
NM_020975.6(RET):c.2372A>T (p.Tyr791Phe)
Germline
Classification
Help
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.
(33)
Help
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.
Benign/Likely benign
33
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.2372A>T (p.Tyr791Phe)
Variation ID: 13936 Accession: VCV000013936.73
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 10q11.21 10: 43118460 (GRCh38) [ NCBI UCSC ] 10: 43613908 (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 Apr 12, 2013 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_020975.6:c.2372A>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_066124.1:p.Tyr791Phe missense NM_000323.2:c.2372A>T NP_000314.1:p.Tyr791Phe missense NM_001355216.2:c.1610A>T NP_001342145.1:p.Tyr537Phe missense NM_001406743.1:c.2372A>T NP_001393672.1:p.Tyr791Phe missense NM_001406744.1:c.2372A>T NP_001393673.1:p.Tyr791Phe missense NM_001406759.1:c.2372A>T NP_001393688.1:p.Tyr791Phe missense NM_001406760.1:c.2372A>T NP_001393689.1:p.Tyr791Phe missense NM_001406761.1:c.2243A>T NP_001393690.1:p.Tyr748Phe missense NM_001406762.1:c.2243A>T NP_001393691.1:p.Tyr748Phe missense NM_001406763.1:c.2237A>T NP_001393692.1:p.Tyr746Phe missense NM_001406764.1:c.2243A>T NP_001393693.1:p.Tyr748Phe missense NM_001406765.1:c.2237A>T NP_001393694.1:p.Tyr746Phe missense NM_001406766.1:c.2084A>T NP_001393695.1:p.Tyr695Phe missense NM_001406767.1:c.2084A>T NP_001393696.1:p.Tyr695Phe missense NM_001406768.1:c.2108A>T NP_001393697.1:p.Tyr703Phe missense NM_001406769.1:c.1976A>T NP_001393698.1:p.Tyr659Phe missense NM_001406770.1:c.2084A>T NP_001393699.1:p.Tyr695Phe missense NM_001406771.1:c.1934A>T NP_001393700.1:p.Tyr645Phe missense NM_001406772.1:c.1976A>T NP_001393701.1:p.Tyr659Phe missense NM_001406773.1:c.1934A>T NP_001393702.1:p.Tyr645Phe missense NM_001406774.1:c.1847A>T NP_001393703.1:p.Tyr616Phe missense NM_001406775.1:c.1646A>T NP_001393704.1:p.Tyr549Phe missense NM_001406776.1:c.1646A>T NP_001393705.1:p.Tyr549Phe missense NM_001406777.1:c.1646A>T NP_001393706.1:p.Tyr549Phe missense NM_001406778.1:c.1646A>T NP_001393707.1:p.Tyr549Phe missense NM_001406779.1:c.1475A>T NP_001393708.1:p.Tyr492Phe missense NM_001406780.1:c.1475A>T NP_001393709.1:p.Tyr492Phe missense NM_001406781.1:c.1475A>T NP_001393710.1:p.Tyr492Phe missense NM_001406782.1:c.1475A>T NP_001393711.1:p.Tyr492Phe missense NM_001406783.1:c.1346A>T NP_001393712.1:p.Tyr449Phe missense NM_001406784.1:c.1382A>T NP_001393713.1:p.Tyr461Phe missense NM_001406785.1:c.1355A>T NP_001393714.1:p.Tyr452Phe missense NM_001406786.1:c.1346A>T NP_001393715.1:p.Tyr449Phe missense NM_001406787.1:c.1340A>T NP_001393716.1:p.Tyr447Phe missense NM_001406788.1:c.1187A>T NP_001393717.1:p.Tyr396Phe missense NM_001406789.1:c.1187A>T NP_001393718.1:p.Tyr396Phe missense NM_001406790.1:c.1187A>T NP_001393719.1:p.Tyr396Phe missense NM_001406791.1:c.1067A>T NP_001393720.1:p.Tyr356Phe missense NM_001406792.1:c.923A>T NP_001393721.1:p.Tyr308Phe missense NM_001406793.1:c.923A>T NP_001393722.1:p.Tyr308Phe missense NM_001406794.1:c.923A>T NP_001393723.1:p.Tyr308Phe missense NM_020629.2:c.2372A>T NP_065680.1:p.Tyr791Phe missense NM_020630.7:c.2372A>T NP_065681.1:p.Tyr791Phe missense NC_000010.11:g.43118460A>T NC_000010.10:g.43613908A>T NG_007489.1:g.46392A>T LRG_518:g.46392A>T LRG_518t1:c.2372A>T LRG_518p1:p.Tyr791Phe LRG_518t2:c.2372A>T LRG_518p2:p.Tyr791Phe P07949:p.Tyr791Phe - Protein change
- Y791F, Y537F, Y447F, Y452F, Y461F, Y549F, Y616F, Y695F, Y703F, Y746F, Y748F, Y396F, Y492F, Y449F, Y645F, Y659F, Y308F, Y356F
- Other names
-
p.Y791F:TAT>TTT
- Canonical SPDI
- NC_000010.11:43118459:A:T
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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 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Trans-Omics for Precision Medicine (TOPMed) 0.00111
The Genome Aggregation Database (gnomAD) 0.00178
Exome Aggregation Consortium (ExAC) 0.00180
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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. |
|---|---|---|---|---|
| Uncertain significance (1) |
no assertion criteria provided
|
Nov 1, 2005 | RCV000014962.36 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000014963.43 | |
| Likely benign (3) |
no assertion criteria provided
|
Jun 1, 2014 | RCV000148769.15 | |
| Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Mar 26, 2020 | RCV000130367.16 | |
| Likely benign (3) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000034771.47 | |
| Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
|
Aug 15, 2023 | RCV000235206.33 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000312825.16 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000370653.14 | |
| Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000400976.13 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000419149.9 | |
| Likely benign (4) |
criteria provided, multiple submitters, no conflicts
|
Apr 18, 2023 | RCV000436831.11 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000426589.9 | |
| Likely benign (3) |
criteria provided, single submitter
|
Jan 1, 2019 | RCV000431156.14 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
May 13, 2016 | RCV000441584.9 | |
| no classifications from unflagged records (1) |
no classifications from unflagged records
|
Oct 12, 2023 | RCV000754613.10 | |
| Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 31, 2024 | RCV001083710.14 | |
| click to load more click to collapse | ||||
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. |
|
|---|---|---|---|---|---|
|
Likely benign
(-)
|
criteria provided, single submitter
Method: clinical testing
|
NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000313719.2
First in ClinVar: Oct 02, 2016 Last updated: May 13, 2023 |
|
|
|
Likely benign
(Mar 31, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000605029.7
First in ClinVar: Dec 06, 2016 Last updated: Mar 04, 2023 |
|
|
|
Benign
(Sep 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000234938.11
First in ClinVar: Jul 05, 2015 Last updated: Apr 09, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
|
|
Likely benign
(May 15, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Counsyl
Accession: SCV000785142.2
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Likely benign
(May 16, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000225910.5
First in ClinVar: Jun 29, 2015 Last updated: May 03, 2018 |
Number of individuals with the variant: 6
Sex: mixed
|
|
|
Likely benign
(May 28, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001138032.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Pheochromocytoma
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362348.3
First in ClinVar: Dec 06, 2016 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)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362351.3
First in ClinVar: Dec 06, 2016 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Hirschsprung disease, susceptibility to, 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362350.3
First in ClinVar: Dec 06, 2016 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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Renal hypodysplasia/aplasia 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000362349.3
First in ClinVar: Dec 06, 2016 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)
|
|
|
Likely benign
(Jan 01, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2B
Affected status: yes
Allele origin:
unknown
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440341.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
|
|
|
Benign
(Dec 08, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001338437.2
First in ClinVar: Jun 22, 2020 Last updated: Jan 09, 2021 |
Comment:
Variant summary: RET c.2372A>T (p.Tyr791Phe) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: RET c.2372A>T (p.Tyr791Phe) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251108 control chromosomes (gnomAD). The observed variant frequency is approximately 56-fold the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. c.2372A>T has been reported in the literature in individuals affected with medullary thyroid carcinoma, pheochromocytoma and Hirschsprung Disease (e.g. Berndt_1998, Elisei_2019, Neumann_2002, Seri_1997, Tamanaha_2007), but also in unaffected controls (e.g. Amendola_2015). Importantly, the variant was found not to segregate with disease in multiple family studies that included unaffected carriers (e.g. Berndt_1998, Elisei_2019, Vestergaard_2007). In addition, co-occurrences with other pathogenic variants have been reported in several affected families (e.g. RET c.1901G>A, p.Cys634Tyr; Valente_2013), providing further supporting evidence for a benign role. Toledo et al (2015) carried out a comprehensive evaluation of the variant through analysis of control data and germline and somatic occurrences in affected individuals/families in an extensive literature review and concluded that, even though limited data in early studies had initially led to the misclassification of RET Y791F as a probable pathogenic variant, the variant on its own does not associate with disease. Fifteen other ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments, including benign/likely benign (n=12), uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign. (less)
|
|
|
Benign
(Jul 01, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000711345.2
First in ClinVar: Apr 09, 2018 Last updated: May 29, 2021 |
Comment:
The p.Tyr791Phe variant in RET has been reported in individuals with a variety of disorders (MEN, FMTC, pheochromocytoma and paraganglioma) including an individual with central … (more)
The p.Tyr791Phe variant in RET has been reported in individuals with a variety of disorders (MEN, FMTC, pheochromocytoma and paraganglioma) including an individual with central hypoventilation syndrome and Hirschsprung disease (Fitze 2003 PMID: 12566528) but is classified as benign because it has been identified in 1.57% (163/10356) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1. (less)
Number of individuals with the variant: 1
|
|
|
Benign
(Aug 14, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV002068567.1
First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022 |
|
|
|
Benign
(Mar 26, 2020)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002529972.1
First in ClinVar: Mar 25, 2020 Last updated: Mar 25, 2020 |
|
|
|
Likely benign
(Apr 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia type 2A
Affected status: unknown
Allele origin:
unknown
|
Myriad Genetics, Inc.
Accession: SCV004018073.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
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)
|
|
|
Likely benign
(Aug 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Accession: SCV004027573.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
|
|
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Benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000166616.14
First in ClinVar: Jun 15, 2014 Last updated: Feb 14, 2024 |
|
|
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Benign
(Sep 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Multiple endocrine neoplasia, type 2
Affected status: unknown
Allele origin:
germline
|
Color Diagnostics, LLC DBA Color Health
Accession: SCV004357246.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
|
|
|
Likely benign
(Mar 29, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000185220.9
First in ClinVar: Aug 06, 2014 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
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001147870.27
First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024 |
Comment:
RET: PM5, BS1
Number of individuals with the variant: 33
|
|
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Uncertain significance
(Nov 01, 2005)
|
no assertion criteria provided
Method: literature only
|
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000035218.3
First in ClinVar: Apr 04, 2013 Last updated: Apr 20, 2024 |
Comment on evidence:
This variant, formerly titled THYROID CARCINOMA, FAMILIAL MEDULLARY, with an included title of PHEOCHROMOCYTOMA, has been reclassified as a variant of unknown significance based on … (more)
This variant, formerly titled THYROID CARCINOMA, FAMILIAL MEDULLARY, with an included title of PHEOCHROMOCYTOMA, has been reclassified as a variant of unknown significance based on the reports of Toledo et al. (2015) and Hoxbroe Michaelsen et al. (2019) and a review of the gnomAD database by Hamosh (2024). In a patient with sporadic pheochromocytoma (171300), Neumann et al. (2002) identified the tyr791-to-phe (Y791F) substitution resulting from a 2372A-T transversion in exon 13 of the RET gene. The mutation was not identified in 600 control chromosomes. Baumgartner-Parzer et al. (2005) found that in patients with familial medullary thyroid carcinoma, the Y791F mutation (which the authors referred to as PHE791TYR, F791Y) was associated with the nearby L769L SNP. All 12 individuals carrying Y791F (9 unrelated individuals and 3 descendants) were homozygous or heterozygous for the L769L polymorphism. Frank-Raue et al. (2005) found this mutation coincident with a splice site mutation in MEN1 (131100.0034) in 3 members of a family with a multiple endocrine neoplasia phenotype. The RET Y791F mutation was carried in isolation by the father, who at 65 years of age had no thyroid or parathyroid disease and no pheochromocytoma, and no family history of medullary thyroid carcinoma, pheochromocytoma, or primary hyperparathyroidism. The authors concluded that the RET Y791F mutation and the MEN1 mutation did not interact. Toledo et al. (2015) detected the Y791F variant in a cohort of 2,904 cancer-free elderly individuals. In addition, the variant traveled in cis with the C634Y variant (164761.0001), which is known to cause aggressive medullary thyroid carcinoma. Hoxbroe Michaelsen et al. (2019) followed a cohort of 20 Danish RET Y791F carriers, none of whom had any evidence of MEN2A at ages 7 to 87 years. Hamosh (2024) noted that the Y279F variant had an overall population frequency of 0.001409 and 10 times that among Ashkenazi Jews in the gnomAD database (v4.0), far exceeding the frequency of the condition. (less)
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no known pathogenicity
(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: SCV000043476.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Benign.
Number of individuals with the variant: 8
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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Likely benign
(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: SCV000190506.1 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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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia type 4
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510482.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Medullary thyroid carcinoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510484.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia, type 1
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000510486.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia type 2A
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510483.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Likely pathogenic
(May 13, 2016)
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no assertion criteria provided
Method: literature only
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Multiple endocrine neoplasia type 2B
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
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Database of Curated Mutations (DoCM)
Accession: SCV000510485.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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Pathogenic
(Aug 28, 2006)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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Hirschsprung disease
Affected status: yes
Allele origin:
germline
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Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital
Accession: SCV000804922.1
First in ClinVar: Dec 06, 2014 Last updated: Dec 06, 2014 |
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Likely pathogenic
(Jan 01, 2013)
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Flagged submission
flagged submission
Method: research
Reason: Older claim that does not account for recent evidence
Source: ClinGen
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Hirschsprung disease
Affected status: yes
Allele origin:
unknown
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Human Genomics Unit, Institute for molecular medicine Finland (FIMM)
Accession: SCV000864574.1
First in ClinVar: Jan 22, 2019 Last updated: Jan 22, 2019 |
Number of individuals with the variant: 3
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Pathogenic
(May 16, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Familial cancer of breast
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
inherited
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Clinical Cancer Genetics and Family Consultants, Athens Medical Center
Accession: SCV000864241.1
First in ClinVar: Jan 28, 2019 Last updated: Jan 28, 2019 |
Comment:
This mutation was observed in a patient affected with metachronous bilateral BC (age 44 and 60). Her sister was diagnosed with BC at the age … (more)
This mutation was observed in a patient affected with metachronous bilateral BC (age 44 and 60). Her sister was diagnosed with BC at the age of 45 and carried the same mutation. A first cousin had also BC at the age of 56, and their father died of gastric cancer at an old age. This is a rare variant with ExAC frequency 0.00180. This mutation is observed for the first time in Greek population. In-silico data indicate this variant to be damaging. It has been showed to be pathogenic in RET-Famillial Medullary Thyroid Carcinoma, PMID: 15753368. We consider this variant to be pathogenic for inherited breast cancer. (less)
Number of individuals with the variant: 2
Clinical Features:
HEREDITARY BREAST CANCER (present)
Age: 44-45 years
Sex: female
Ethnicity/Population group: GREEK
Geographic origin: Greece
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Uncertain significance
(Nov 21, 2018)
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Flagged submission
flagged submission
Method: clinical testing
Reason: Outlier claim with insufficient supporting evidence
Source: ClinGen
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Multiple endocrine neoplasia type 2B
Affected status: unknown
Allele origin:
unknown
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Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Accession: SCV000883125.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
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| Flagged submissions do not contribute to the aggregate classification or review status for the variant. Learn more | |||||
Citation text
Hamosh, A. Personal Communication. 2024. Baltimore, Md.
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
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, 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.
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, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, 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.
Comment:
Variant summary: RET c.2372A>T (p.Tyr791Phe) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251108 control chromosomes (gnomAD). The observed variant frequency is approximately 56-fold the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. c.2372A>T has been reported in the literature in individuals affected with medullary thyroid carcinoma, pheochromocytoma and Hirschsprung Disease (e.g. Berndt_1998, Elisei_2019, Neumann_2002, Seri_1997, Tamanaha_2007), but also in unaffected controls (e.g. Amendola_2015). Importantly, the variant was found not to segregate with disease in multiple family studies that included unaffected carriers (e.g. Berndt_1998, Elisei_2019, Vestergaard_2007). In addition, co-occurrences with other pathogenic variants have been reported in several affected families (e.g. RET c.1901G>A, p.Cys634Tyr; Valente_2013), providing further supporting evidence for a benign role. Toledo et al (2015) carried out a comprehensive evaluation of the variant through analysis of control data and germline and somatic occurrences in affected individuals/families in an extensive literature review and concluded that, even though limited data in early studies had initially led to the misclassification of RET Y791F as a probable pathogenic variant, the variant on its own does not associate with disease. Fifteen other ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments, including benign/likely benign (n=12), uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign.
Comment:
The p.Tyr791Phe variant in RET has been reported in individuals with a variety of disorders (MEN, FMTC, pheochromocytoma and paraganglioma) including an individual with central hypoventilation syndrome and Hirschsprung disease (Fitze 2003 PMID: 12566528) but is classified as benign because it has been identified in 1.57% (163/10356) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
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 prevalence and penetrance.
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:
RET: PM5, BS1
Comment:
Converted during submission to Benign.
Comment:
This mutation was observed in a patient affected with metachronous bilateral BC (age 44 and 60). Her sister was diagnosed with BC at the age of 45 and carried the same mutation. A first cousin had also BC at the age of 56, and their father died of gastric cancer at an old age. This is a rare variant with ExAC frequency 0.00180. This mutation is observed for the first time in Greek population. In-silico data indicate this variant to be damaging. It has been showed to be pathogenic in RET-Famillial Medullary Thyroid Carcinoma, PMID: 15753368. We consider this variant to be pathogenic for inherited breast cancer.
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:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
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, 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.
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, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
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, 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.
Comment:
Variant summary: RET c.2372A>T (p.Tyr791Phe) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 251108 control chromosomes (gnomAD). The observed variant frequency is approximately 56-fold the estimated maximal expected allele frequency for a pathogenic variant in RET causing Multiple Endocrine Neoplasia Type 2 phenotype (3.7e-05), strongly suggesting that the variant is benign. c.2372A>T has been reported in the literature in individuals affected with medullary thyroid carcinoma, pheochromocytoma and Hirschsprung Disease (e.g. Berndt_1998, Elisei_2019, Neumann_2002, Seri_1997, Tamanaha_2007), but also in unaffected controls (e.g. Amendola_2015). Importantly, the variant was found not to segregate with disease in multiple family studies that included unaffected carriers (e.g. Berndt_1998, Elisei_2019, Vestergaard_2007). In addition, co-occurrences with other pathogenic variants have been reported in several affected families (e.g. RET c.1901G>A, p.Cys634Tyr; Valente_2013), providing further supporting evidence for a benign role. Toledo et al (2015) carried out a comprehensive evaluation of the variant through analysis of control data and germline and somatic occurrences in affected individuals/families in an extensive literature review and concluded that, even though limited data in early studies had initially led to the misclassification of RET Y791F as a probable pathogenic variant, the variant on its own does not associate with disease. Fifteen other ClinVar submitters (evaluation after 2014) cite the variant with conflicting assessments, including benign/likely benign (n=12), uncertain significance (n=2) and pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign.
Comment:
The p.Tyr791Phe variant in RET has been reported in individuals with a variety of disorders (MEN, FMTC, pheochromocytoma and paraganglioma) including an individual with central hypoventilation syndrome and Hirschsprung disease (Fitze 2003 PMID: 12566528) but is classified as benign because it has been identified in 1.57% (163/10356) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BA1.
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 prevalence and penetrance.
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:
RET: PM5, BS1
Comment:
Converted during submission to Benign.
Comment:
This mutation was observed in a patient affected with metachronous bilateral BC (age 44 and 60). Her sister was diagnosed with BC at the age of 45 and carried the same mutation. A first cousin had also BC at the age of 56, and their father died of gastric cancer at an old age. This is a rare variant with ExAC frequency 0.00180. This mutation is observed for the first time in Greek population. In-silico data indicate this variant to be damaging. It has been showed to be pathogenic in RET-Famillial Medullary Thyroid Carcinoma, PMID: 15753368. We consider this variant to be pathogenic for inherited breast cancer.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations. | Elisei R | Genes | 2019 | PMID: 31510104 |
| Long-term follow-up of RET Y791F carriers in Denmark 1994-2017: A National Cohort Study. | Høxbroe Michaelsen S | Journal of surgical oncology | 2019 | PMID: 30644554 |
| Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. | Maxwell KN | American journal of human genetics | 2016 | PMID: 27153395 |
| Actionable exomic incidental findings in 6503 participants: challenges of variant classification. | Amendola LM | Genome research | 2015 | PMID: 25637381 |
| Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility. | Toledo RA | Endocrine-related cancer | 2015 | PMID: 25425582 |
| Hereditary paraganglioma-pheochromocytoma syndromes associated with SDHD and RET mutations. | Choi Jdo W | Head & neck | 2014 | PMID: 24375508 |
| Comprehensive analysis of RET gene should be performed in patients with multiple endocrine neoplasia type 2 (MEN 2) syndrome and no apparent genotype-phenotype correlation: an appraisal of p.Y791F and p.C634Y RET mutations in five unrelated Brazilian families. | Valente FO | Journal of endocrinological investigation | 2013 | PMID: 23723040 |
| 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 |
| Molecular mechanisms of RET receptor-mediated oncogenesis in multiple endocrine neoplasia 2. | Wagner SM | Clinics (Sao Paulo, Brazil) | 2012 | PMID: 22584710 |
| In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. | Cosci B | Endocrine-related cancer | 2011 | PMID: 21810974 |
| RET-protooncogene variants in patients with sporadic neoplasms of the digestive tract and the central nervous system. | Rückert F | International journal of colorectal disease | 2011 | PMID: 21311890 |
| High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. | Toledo RA | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 20080836 |
| Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome. | Erlic Z | The Journal of clinical endocrinology and metabolism | 2010 | PMID: 19906784 |
| RET mutation Tyr791Phe: the genetic cause of different diseases derived from neural crest. | Vaclavikova E | Endocrine | 2009 | PMID: 19826964 |
| Y791F RET mutation and early onset of medullary thyroid carcinoma in a Brazilian kindred: evaluation of phenotype-modifying effect of germline variants. | Tamanaha R | Clinical endocrinology | 2007 | PMID: 17610518 |
| Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated? | Vestergaard P | World journal of surgery | 2007 | PMID: 17483988 |
| The risk of medullary thyroid carcinoma in patients with Hirschsprung's disease. | Skába R | Pediatric surgery international | 2006 | PMID: 17021738 |
| Double germline mutations in the RET Proto-oncogene in MEN 2A and MEN 2B kindreds. | Dvorakova S | Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association | 2006 | PMID: 16705552 |
| Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma? | Baumgartner-Parzer SM | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 16118333 |
| Coincidence of multiple endocrine neoplasia types 1 and 2: mutations in the RET protooncogene and MEN1 tumor suppressor gene in a family presenting with recurrent primary hyperparathyroidism. | Frank-Raue K | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 15870131 |
| RET-familial medullary thyroid carcinoma mutants Y791F and S891A activate a Src/JAK/STAT3 pathway, independent of glial cell line-derived neurotrophic factor. | Plaza Menacho I | Cancer research | 2005 | PMID: 15753368 |
| Screening of six risk exons of the RET proto-oncogene in families with medullary thyroid carcinoma in the Czech Republic. | Jindrichová S | The Journal of endocrinology | 2004 | PMID: 15531714 |
| Association of germline mutations and polymorphisms of the RET proto-oncogene with idiopathic congenital central hypoventilation syndrome in 33 patients. | Fitze G | Journal of medical genetics | 2003 | PMID: 12566528 |
| Germ-line mutations in nonsyndromic pheochromocytoma. | Neumann HP | The New England journal of medicine | 2002 | PMID: 12000816 |
| A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. | Berndt I | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9506724 |
| Frequency of RET mutations in long- and short-segment Hirschsprung disease. | Seri M | Human mutation | 1997 | PMID: 9090527 |
| Hamosh, A. Personal Communication. 2024. Baltimore, Md. | - | - | - | - |
| http://docm.genome.wustl.edu/variants/ENST00000340058:c.2372A>T | - | - | - | - |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RET | - | - | - | - |
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Text-mined citations for rs77724903 ...
HelpThese 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
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.