Submissions for variant NM_020975.6(RET):c.1915G>A (p.Ala639Thr)

gnomAD frequency: 0.00001  dbSNP: rs777122776

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226795	SCV000290539	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 639 of the RET protein (p.Ala639Thr). This variant is present in population databases (rs777122776, gnomAD 0.005%). This missense change has been observed in individual(s) with medullary thyroid carcinoma, however in some of these individuals a pathogenic variant was also identified in the RET gene (PMID: 26321248, 33827484). ClinVar contains an entry for this variant (Variation ID: 241341). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine 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.
Counsyl	RCV000409197	SCV000489941	uncertain significance	Multiple endocrine neoplasia type 2B	2016-08-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000410332	SCV000489942	uncertain significance	Multiple endocrine neoplasia type 2A	2016-08-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679725	SCV000807015	uncertain significance	not provided	2017-12-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001013684	SCV001174303	likely benign	Hereditary cancer-predisposing syndrome	2023-03-24	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.
Myriad Genetics, Inc.	RCV000410332	SCV004018037	likely benign	Multiple endocrine neoplasia type 2A	2023-04-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
GeneDx	RCV000679725	SCV004031919	uncertain significance	not provided	2023-03-01	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 14633923, 34757920, 26321248, 33827484, 34687025, 34135865)
Baylor Genetics	RCV003469160	SCV004206740	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-02-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000226795	SCV004823002	uncertain significance	Multiple endocrine neoplasia, type 2	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 639 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 been reported in an individual affected with medullary thyroid cancer (PMID: 26321248) and an individual affected with medullary and papillary thyroid carcinoma that are under 1-cm nodules (PMID: 34687025). This variant also has been observed in cis with a deleterious RET missense variant p.Cys618Arg in three members affected with medullary thyroid cancer in a family (PMID: 33827484). This variant has been identified in 8/279468 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.