ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2372A>T (p.Tyr791Phe) (rs77724903)

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Total submissions: 31
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083710 SCV000166616 benign Multiple endocrine neoplasia, type 2 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130367 SCV000185220 likely benign Hereditary cancer-predisposing syndrome 2019-03-29 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000235206 SCV000225910 likely benign not specified 2018-05-16 criteria provided, single submitter clinical testing
GeneDx RCV000235206 SCV000234938 benign not specified 2017-09-15 criteria provided, single submitter clinical testing 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.
PreventionGenetics,PreventionGenetics RCV000235206 SCV000313719 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000014963 SCV000362348 likely benign Pheochromocytoma 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV000400976 SCV000362349 likely benign Renal hypodysplasia/aplasia 1 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV000312825 SCV000362350 likely benign Hirschsprung disease 1 2017-04-27 criteria provided, single submitter clinical testing 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.
Illumina Clinical Services Laboratory,Illumina RCV000370653 SCV000362351 likely benign Multiple endocrine neoplasia 2017-04-27 criteria provided, single submitter clinical testing 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283270 SCV000605029 likely benign none provided 2019-10-06 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235206 SCV000711345 benign not specified 2020-07-01 criteria provided, single submitter clinical testing 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.
Counsyl RCV000436831 SCV000785142 likely benign Multiple endocrine neoplasia, type 2a 2017-05-15 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034771 SCV000807026 likely benign not provided 2016-05-24 criteria provided, single submitter clinical testing
Clinical Cancer Genetics and Family Consultants,Athens Medical Center RCV000754613 SCV000864241 pathogenic Familial cancer of breast 2018-05-16 criteria provided, single submitter clinical testing 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.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000431156 SCV000883125 uncertain significance Multiple endocrine neoplasia, type 2b 2018-11-21 criteria provided, single submitter clinical testing
Mendelics RCV000436831 SCV001138032 likely benign Multiple endocrine neoplasia, type 2a 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034771 SCV001147870 likely benign not provided 2021-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235206 SCV001338437 benign not specified 2020-12-08 criteria provided, single submitter clinical testing 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000431156 SCV001440341 likely benign Multiple endocrine neoplasia, type 2b 2019-01-01 criteria provided, single submitter clinical testing
OMIM RCV000014962 SCV000035218 pathogenic Familial medullary thyroid carcinoma 2005-11-01 no assertion criteria provided literature only
OMIM RCV000014963 SCV000035219 pathogenic Pheochromocytoma 2005-11-01 no assertion criteria provided literature only
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034771 SCV000043476 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
Research and Development, ARUP Laboratories RCV000235206 SCV000055392 benign not specified 2019-05-01 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148769 SCV000190506 likely benign Hirschsprung disease 2014-06-01 no assertion criteria provided research
Database of Curated Mutations (DoCM) RCV000426589 SCV000510482 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436831 SCV000510483 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419149 SCV000510484 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431156 SCV000510485 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000441584 SCV000510486 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000148769 SCV000804922 pathogenic Hirschsprung disease 2006-08-28 no assertion criteria provided clinical testing
Human Genomics Unit,Institute for molecular medicine Finland (FIMM) RCV000148769 SCV000864574 likely pathogenic Hirschsprung disease 2013-01-01 no assertion criteria provided research

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