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

gnomAD frequency: 0.00178  dbSNP: rs77724903

Total submissions: 33

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083710	SCV000166616	benign	Multiple endocrine neoplasia, type 2	2024-01-31	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	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.
Eurofins Ntd Llc (ga)	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, part of Exact Sciences	RCV000235206	SCV000313719	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Laboratory Services, 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 Laboratory Services, Illumina	RCV000312825	SCV000362350	likely benign	Hirschsprung disease, susceptibility to, 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 Laboratory Services, 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	2022-03-31	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham 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
Mendelics	RCV000436831	SCV001138032	likely benign	Multiple endocrine neoplasia type 2A	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034771	SCV001147870	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RET: PM5, BS1
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
Genetic Services Laboratory, University of Chicago	RCV000235206	SCV002068567	benign	not specified	2019-08-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130367	SCV002529972	benign	Hereditary cancer-predisposing syndrome	2020-03-26	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000436831	SCV004018073	likely benign	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000235206	SCV004027573	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001083710	SCV004357246	benign	Multiple endocrine neoplasia, type 2	2022-09-21	criteria provided, single submitter	clinical testing
OMIM	RCV000014962	SCV000035218	uncertain significance	Familial medullary thyroid carcinoma	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.
CSER _CC_NCGL, University of Washington	RCV000148769	SCV000190506	likely benign	Aganglionic megacolon	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	Aganglionic megacolon	2006-08-28	flagged submission	clinical testing
Clinical Cancer Genetics and Family Consultants, Athens Medical Center	RCV000754613	SCV000864241	pathogenic	Familial cancer of breast	2018-05-16	flagged submission	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.
Human Genomics Unit, Institute for molecular medicine Finland (FIMM)	RCV000148769	SCV000864574	likely pathogenic	Aganglionic megacolon	2013-01-01	flagged submission	research
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000431156	SCV000883125	uncertain significance	Multiple endocrine neoplasia type 2B	2018-11-21	flagged submission	clinical testing