ClinVar Miner

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

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Total submissions: 30
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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 2019-12-31 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 RCV000034771 SCV000605029 likely benign not provided 2018-03-14 criteria provided, single submitter clinical testing The RET c.2372A>T; p.Tyr791Phe variant (rs77724903) was first reported in patients with Hirschsprung disease (Seri 1997), medullary thyroid carcinomas (Berndt 1998, Tamanaha 2007) and pheochromocytoma (Neumann 2002). However, subsequent studies identified the variant to be present at similar frequencies in unaffected individuals (Vierhapper 2004, Vestergaard 2007, Erlic 2010, Toledo 2015) and higher than expected for the disorder (Amendola 2015, Toledo 2015). The variant did not co-segregate with disease (Vestergaard 2007, Erlic 2010), and has been identified in cases co-occurring with a pathogenic variant that is predicted to be causative (Toledo 2010, Peczkowska 2013). This variant is reported in ClinVar (Variation ID: 13936) and is observed in the general population at an overall frequency of 0.2% (595/277024 alleles, 1 homozygote), with increased frequency in the Ashkenazi Jewish population (1.6%) in the Genome Aggregation Database. The tyrosine at codon 791 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. However, functional studies demonstrate the variant protein to be similar to wildtype in activity and cellular effects (Cosci 2011, Hyndman 2012). Based on available information, this variant is considered likely benign. References: Amendola L et al. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res. 2015;25(3):305-15. Berndt I et al. A new hot spot for mutations in the ret protooncogene causing familial medullary thyroid carcinoma and multiple endocrine neoplasia type 2A. J Clin Endocrinol Metab. 1998;83(3):770-4. Cosci B et al. In silico and in vitro analysis of rare germline allelic variants of RET oncogene associated with medullary thyroid cancer. Endocr Relat Cancer. 2011;18(5):603-12. Erlic Z et al. Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome. J Clin Endocrinol Metab. 2010;95(1):308-13. Hyndman B et al. Multiple functional effects of RET kinase domain sequence variants in Hirschsprung disease. Hum Mutat. 2013;34(1):132-42. Neumann H et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346(19):1459-66. Peczkowska M et al. Testing new susceptibility genes in the cohort of apparently sporadic phaeochromocytoma/paraganglioma patients with clinical characteristics of hereditary syndromes. Clin Endocrinol (Oxf). 2013;79(6):817-23. Seri M et al. Frequency of RET mutations in long- and short-segment Hirschsprung disease. Hum Mutat. 1997;9(3):243-9. Tamanaha R et al. Y791F RET mutation and early onset of medullary thyroid carcinoma in a Brazilian kindred: evaluation of phenotype-modifying effect of germline variants. Clin Endocrinol (Oxf). 2007;67(5):806-8. Toledo R et al. High penetrance of pheochromocytoma associated with the novel C634Y/Y791F double germline mutation in the RET protooncogene. J Clin Endocrinol Metab. 2010;95(3):1318-27. Toledo R et al. Comprehensive assessment of the disputed RET Y791F variant shows no association with medullary thyroid carcinoma susceptibility. Endocr Relat Cancer. 2015;22(1):65-76. Vestergaard P et al. Codon Y791F mutations in a large kindred: is prophylactic thyroidectomy always indicated? World J Surg. 2007;31(5):996-1001. Vierhapper H et al. Frequency of RET proto-oncogene mutations in patients with normal and with moderately elevated pentagastrin-stimulated serum concentrations of calcitonin. Thyroid. 2004;14(8):580-3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235206 SCV000711345 likely benign not specified 2016-06-21 criteria provided, single submitter clinical testing The p.Tyr791Phe variant in RET has been reported in individuals with a variety o f disorders (MEN, FMTC, pheochromocytoma and paraganglioma) including an individ ual with central hypoventilation syndrome and Hirschsprung disease (Fitze 2003). However, it is highly unlikely that this variant is disease causing for penetra nt Mendelian disease given its prevalence in the general population (up to 0.6%; 38/6558 Finnish chromosomes (ExAC, http://exac.broadinstitute.org; dbSNP rs7772 4903). In summary, the frequency of this variant indicates that it is likely ben ign.
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 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235206 SCV001338437 benign not specified 2020-04-29 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 of 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 demonstrated to not associate or segregate with disease in different families examined with multiple unaffected carrier members (e.g. Berndt_1998, Elisei_2019, Vestergaard_2007). 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, somatic occurrences, germline occurrences in affected individuals/families and extensive literature review and concluded that even though limited analyses by previous studies had initially led to the misclassification of RET Y791F as a probable pathogenic variant, their evaluation comprehensively revealed that the variant on its own is not associated with disease. Fifteen ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign (n=11), as uncertain significance (n=2) and as pathogenic/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as benign.
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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