Submissions for variant NM_020975.6(RET):c.2548G>T (p.Asp850Tyr)

gnomAD frequency: 0.00001  dbSNP: rs772862503

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217246	SCV000278113	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-09	criteria provided, single submitter	clinical testing	The p.D850Y variant (also known as c.2548G>T), located in coding exon 14 of the RET gene, results from a G to T substitution at nucleotide position 2548. The aspartic acid at codon 850 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000469457	SCV000543835	uncertain significance	Multiple endocrine neoplasia, type 2	2024-11-12	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 850 of the RET protein (p.Asp850Tyr). This variant is not present in population databases (gnomAD no frequency). 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: 233687). 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 disruptive. 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	RCV002464149	SCV002759200	uncertain significance	not provided	2022-06-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 14633923)
All of Us Research Program, National Institutes of Health	RCV000469457	SCV004818849	uncertain significance	Multiple endocrine neoplasia, type 2	2024-07-29	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with tyrosine at codon 850 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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 disorders in the literature. This variant has not been identified 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.
Baylor Genetics	RCV004567649	SCV005054187	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-02-23	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV005055093	SCV005689269	uncertain significance	Multiple endocrine neoplasia type 2A	2024-09-23	criteria provided, single submitter	clinical testing	The RET c.2548G>T (p.Asp850Tyr) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type II. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.