ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2711C>T (p.Ser904Phe) (rs267607011)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757722 SCV000886056 likely pathogenic not provided 2017-06-18 criteria provided, single submitter clinical testing The RET c.2711C>T;p.Ser904Phe variant has been published in at least one family with medullary thyroid carcinoma (Cosci 2011, Elisei 2007). The variant has also been shown to perform similarly to known pathogenic variants in at least one in vitro study (Cosci 2011). Additionally, this variant is located in the tyrosine kinase domain, immediately adjacent to tyrosine 905, which is critical in several of the protein's functions (Arighi 2005). The variant is described in the ClinVar database (Variation ID: 24963) and the dbSNP variant database (rs267607011), but not in the general population abased databases (Exome Variant Server, Genome Aggregation Database). The amino acid at this position is highly conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Considering available information, this variant is classified as likely pathogenic. References: Arighi E et al. RET tyrosine kinase signaling in development and cancer. Cytokine Growth Factor Rev. 2005 Aug-Oct;16(4-5):441-67. 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 Sep 20;18(5):603-12. Elisei R et al. RET genetic screening in patients with medullary thyroid cancer and their relatives: experience with 807 individuals at one center. J Clin Endocrinol Metab. 2007 Dec;92(12):4725-9.
Division of Medical Genetics,Azienda Ospedaliero-Universitaria Policlinico S. Orsola-Malpighi RCV001267835 SCV001445817 likely pathogenic Multiple endocrine neoplasia, type 2a 2020-11-20 criteria provided, single submitter clinical testing The p.Ser904Phe variant, previously reported in one family with father and son affected by adult-onset MTC and hypothesized as belonging to the lowest risk level based on results of in silico and in vitro analyses (Cosci et al 2011, Elisei et al 2019), was identified in ten individuals from a single family, seven of whom affected by adult-onset MTC. Thus, the availability of several genetically and clinically characterized members allowed to provide evidence that the p.Ser904Phe variant is highly penetrant but leads to the development of slowly-progressing MTC at relatively advanced age.
Research and Development, ARUP Laboratories RCV000021878 SCV000042544 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only First report, single Italian individual: MTC only (40 yr). Second report, single family, 2 with mutation: two MTC. In vitro studies: PMID 21810974.

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