Submissions for variant NM_020975.6(RET):c.2607+4C>T

gnomAD frequency: 0.00015  dbSNP: rs200634990

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199849	SCV000255049	uncertain significance	Multiple endocrine neoplasia, type 2	2024-11-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 of the RET gene. It does not directly change the encoded amino acid sequence of the RET protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200634990, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RET-related conditions. ClinVar contains an entry for this variant (Variation ID: 216720). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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	RCV000409038	SCV000490047	uncertain significance	Multiple endocrine neoplasia type 2B	2016-10-13	criteria provided, single submitter	clinical testing
Counsyl	RCV000410597	SCV000490048	uncertain significance	Multiple endocrine neoplasia type 2A	2016-10-13	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001016043	SCV001176954	likely benign	Hereditary cancer-predisposing syndrome	2018-12-28	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.	RCV000410597	SCV004018470	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477672	SCV004220043	uncertain significance	not provided	2024-11-05	criteria provided, single submitter	clinical testing	The RET c.2607+4C>T variant has been reported in the published literature in individuals with a personal and/or family history of breast cancer (PMID: 35957908 (2022), 35534704 (2022)). The frequency of this variant in the general population, 0.00028 (10/35386 chromosomes in Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on RET mRNA splicing yielded inconclusive findings. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000199849	SCV004820555	uncertain significance	Multiple endocrine neoplasia, type 2	2024-07-29	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide substitution at the +4 position of intron 14 of the RET gene. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with RET-related disorders in the literature. This variant has been identified in 14/280052 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.
Fulgent Genetics, Fulgent Genetics	RCV005031750	SCV005671999	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2024-06-10	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004530197	SCV004715313	likely benign	RET-related disorder	2022-06-27	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).