Submissions for variant NM_020975.6(RET):c.2641C>G (p.Leu881Val)

dbSNP: rs377767427

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410267	SCV000489787	uncertain significance	Multiple endocrine neoplasia, type 2b	2016-02-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000410921	SCV000489788	uncertain significance	Multiple endocrine neoplasia, type 2a	2016-02-16	criteria provided, single submitter	clinical testing
Invitae	RCV000466832	SCV000543803	uncertain significance	Multiple endocrine neoplasia, type 2	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 881 of the RET protein (p.Leu881Val). This variant is present in population databases (rs377767427, gnomAD 0.003%). This missense change has been observed in individual(s) with medullary thyroid carcinoma, C-cell hyperplasia, and cancer (PMID: 20013610). ClinVar contains an entry for this variant (Variation ID: 24957). 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	RCV000569942	SCV000664472	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-29	criteria provided, single submitter	clinical testing	The p.L881V variant (also known as c.2641C>G), located in coding exon 15 of the RET gene, results from a C to G substitution at nucleotide position 2641. The leucine at codon 881 is replaced by valine, an amino acid with highly similar properties. This alteration was previously identified in an individual with medullary thyroid cancer, as well as both asymptomatic and symptomatic family members, prompting authors to suggest that the alteration is a low risk mutation associated with late onset and incomplete penetrance (Frank-Raue K, et al. Exp. Clin. Endocrinol. Diabetes. 2010 Aug;118:550-3). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001753425	SCV001986037	uncertain significance	not provided	2019-04-08	criteria provided, single submitter	clinical testing	Observed in an individual with medullary thyroid microcarcinoma, a relative with C-cell hyperplasia, and two unaffected relatives (Frank-Raue et al., 2010); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21479187, 1479187, 20013610)
Myriad Genetics, Inc.	RCV000410921	SCV004018492	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.