Submissions for variant NM_020975.6(RET):c.1142T>G (p.Phe381Cys)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002610618	SCV003495191	uncertain significance	Multiple endocrine neoplasia, type 2	2024-03-09	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 381 of the RET protein (p.Phe381Cys). 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: 2178070). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV004771532	SCV005382283	uncertain significance	Familial medullary thyroid carcinoma	2023-05-20	criteria provided, single submitter	clinical testing	The observed missense variant c.1142T>G (p.Phe381Cys) in the RET gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant is absent in the gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. However, no details are available for independent assessment. The amino acid Phenylalanine at position 381 is changed to a Cysteine changing protein sequence and it might alter its composition and physico- chemical properties. Multiple lines of computational evidence (Polyphen - Probably damaging, SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Ambry Genetics	RCV004942992	SCV005490984	uncertain significance	Hereditary cancer-predisposing syndrome	2024-12-05	criteria provided, single submitter	clinical testing	The p.F381C variant (also known as c.1142T>G), located in coding exon 6 of the RET gene, results from a T to G substitution at nucleotide position 1142. The phenylalanine at codon 381 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005034727	SCV005666152	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2024-03-06	criteria provided, single submitter	clinical testing