ClinVar Miner

Submissions for variant NM_020975.6(RET):c.2497C>T (p.Arg833Cys) (rs377767422)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567481 SCV000674804 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000662806 SCV000785639 uncertain significance Multiple endocrine neoplasia, type 2a 2017-10-17 criteria provided, single submitter clinical testing
GeneDx RCV000478761 SCV000568558 uncertain significance not provided 2018-03-27 criteria provided, single submitter clinical testing This variant is denoted RET c.2497C>T at the cDNA level, p.Arg833Cys (R833C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). Although this variant has been published as occurring in two individuals with medullary thyroid carcinoma (MTC), one of whom also had a family history of MTC (FMTC), multiple internal and external individuals referred for clinical testing for inherited cancer susceptibility did not exhibit phenotypes consistent with a RET-related presentation (Cranston 2006, Romei 2015, ClinVar SCV000658454.1, ClinVar SCV000674804.1). In functional studies, R833C displayed results similar to known MTC moderate-risk variants V804L and S891A, including transformation potential, tumor formation, low-level activating potential, a mild increase in kinase activity, and no invasion (Cranston 2006); however, the clinical implications of these results are unknown. RET Arg833Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the tyrosine kinase domain (Garcia-Barcelo 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RET Arg833Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000529442 SCV000658454 uncertain significance Multiple endocrine neoplasia, type 2 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 833 of the RET protein (p.Arg833Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs377767422, ExAC 0.003%). This variant has been reported in two individuals affected with affected with medullary thyroid carcinoma (PMID: 16469774, 25440022). ClinVar contains an entry for this variant (Variation ID: 24945). Experimental studies have shown that this missense change is weakly activating and has transforming capability in the long 3' splice isoform, but lacks invasion potential (PMID: 16469774). The clinical significance of these findings is uncertain. In summary, this variant has uncertain impact on RET function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Research and Development, ARUP Laboratories RCV000021859 SCV000042525 uncertain significance not specified 2018-05-04 no assertion criteria provided literature only Single individual report: MTC only at 59 yr. In vitro studies: low RET activation.

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