Submissions for variant NM_020975.6(RET):c.1016C>T (p.Ser339Leu)

gnomAD frequency: 0.00002  dbSNP: rs774829203

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000663096	SCV000786201	uncertain significance	Multiple endocrine neoplasia type 2A	2018-03-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000818592	SCV000959214	uncertain significance	Multiple endocrine neoplasia, type 2	2024-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 339 of the RET protein (p.Ser339Leu). This variant is present in population databases (rs774829203, gnomAD 0.007%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22174939). ClinVar contains an entry for this variant (Variation ID: 548870). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV002343411	SCV002645945	likely benign	Hereditary cancer-predisposing syndrome	2022-03-14	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.
Fulgent Genetics, Fulgent Genetics	RCV002485508	SCV002778813	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2021-11-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000663096	SCV004018054	uncertain significance	Multiple endocrine neoplasia type 2A	2023-04-17	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	RCV000818592	SCV004833923	uncertain significance	Multiple endocrine neoplasia, type 2	2023-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 339 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related multiple endocrine neoplasia or medullary thyroid cancer in the literature. This variant has been identified in 2/249444 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.