Submissions for variant NM_020975.6(RET):c.509C>T (p.Thr170Ile)

gnomAD frequency: 0.00004  dbSNP: rs200547906

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000410582	SCV000489905	uncertain significance	Multiple endocrine neoplasia type 2B	2016-07-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000411681	SCV000489906	uncertain significance	Multiple endocrine neoplasia type 2A	2016-07-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701145	SCV000829929	uncertain significance	Multiple endocrine neoplasia, type 2	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 170 of the RET protein (p.Thr170Ile). This variant is present in population databases (rs200547906, gnomAD 0.004%). 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: 41844). 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.
Ambry Genetics	RCV001023532	SCV001185431	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-28	criteria provided, single submitter	clinical testing	The p.T170I variant (also known as c.509C>T), located in coding exon 3 of the RET gene, results from a C to T substitution at nucleotide position 509. The threonine at codon 170 is replaced by isoleucine, an amino acid with similar properties. This variant was detected as a secondary finding in one out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am J Hum Genet, 2012 Jul;91:97-108). 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.
All of Us Research Program, National Institutes of Health	RCV000701145	SCV004827582	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000034776	SCV005383994	uncertain significance	not provided	2023-12-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with atherosclerosis undergoing whole exome sequencing (PMID: 22703879); This variant is associated with the following publications: (PMID: 14633923, 22703879)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034776	SCV005623118	uncertain significance	not provided	2024-03-22	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034776	SCV000043469	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.