Submissions for variant NM_020975.6(RET):c.2531G>T (p.Arg844Leu)

dbSNP: rs55947360

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000409297	SCV000490007	uncertain significance	Multiple endocrine neoplasia type 2B	2016-09-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000410406	SCV000490008	uncertain significance	Multiple endocrine neoplasia type 2A	2016-09-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460812	SCV000543811	uncertain significance	Multiple endocrine neoplasia, type 2	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 844 of the RET protein (p.Arg844Leu). This variant is present in population databases (rs55947360, gnomAD 0.002%). This missense change has been observed in individual(s) with medullary thyroid cancer (PMID: 10826520, 28946813). ClinVar contains an entry for this variant (Variation ID: 24952). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002426514	SCV002740537	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-14	criteria provided, single submitter	clinical testing	The p.R844L variant (also known as c.2531G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide position 2531. The arginine at codon 844 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in individuals with familial medullary thyroid cancer; however, these individuals also carried another RET mutation, p.V804M (Bartsch DK et al. Exp Clin Endocrinol Diabetes 2000 ;108(2):128-32; Lebeault M et al. Thyroid 2017 12;27(12):1511-1522). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Myriad Genetics, Inc.	RCV000410406	SCV004018469	uncertain significance	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV000460812	SCV005430387	uncertain significance	Multiple endocrine neoplasia, type 2	2024-06-09	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 844 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in cis with a deleterious RET p.Val804Met covariant in a familial medullary thyroid cancer family (PMID: 10826520) and has been speculated to be a modifier of the p.Val804Met covariant (PMID: 21655256). This variant has been identified in 2/282062 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.