Submissions for variant NM_020975.6(RET):c.884C>T (p.Thr295Met)

gnomAD frequency: 0.00001  dbSNP: rs758159521

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001018407	SCV001179642	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-07	criteria provided, single submitter	clinical testing	The p.T295M variant (also known as c.884C>T), located in coding exon 5 of the RET gene, results from a C to T substitution at nucleotide position 884. The threonine at codon 295 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040270	SCV001203833	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 295 of the RET protein (p.Thr295Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with medullary thyroid cancer and pheochromocytoma (PMID: 28946813, 30877234). ClinVar contains an entry for this variant (Variation ID: 549769). 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 tolerated. 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.
GeneDx	RCV001779040	SCV002015443	uncertain significance	not provided	2021-05-07	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Observed in individuals with a personal or family history including medullary thyroid carcinoma and phenochromocytoma (Lebeault 2017, Ben Aim 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30877234, 28946813)
PreventionGenetics, part of Exact Sciences	RCV004527722	SCV004106087	uncertain significance	RET-related disorder	2023-10-11	criteria provided, single submitter	clinical testing	The RET c.884C>T variant is predicted to result in the amino acid substitution p.Thr295Met. This variant has been reported in an individual with medullary thyroid cancer and an individual with phaeochromocytoma (Table 2, Lebeault et al. 2017. PubMed ID: 28946813; Table S3, Ben Aim et al. 2019. PubMed ID: 30877234). This variant is reported in 2 of ~247,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/10-43601840-C-T). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/549769/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Myriad Genetics, Inc.	RCV004792356	SCV005403666	likely benign	Multiple endocrine neoplasia type 2A	2024-09-04	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.