Submissions for variant NM_020975.6(RET):c.1267G>T (p.Gly423Trp)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325287	SCV004031213	uncertain significance	Multiple endocrine neoplasia type 2A	2023-05-23	criteria provided, single submitter	clinical testing	The RET c.1267G>T (p.Gly423Trp) missense change has a maximum subpopulation frequency of 0.006% 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.
Ambry Genetics	RCV003358163	SCV004056422	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-24	criteria provided, single submitter	clinical testing	The p.G423W variant (also known as c.1267G>T), located in coding exon 7 of the RET gene, results from a G to T substitution at nucleotide position 1267. The glycine at codon 423 is replaced by tryptophan, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.