Submissions for variant NM_020975.6(RET):c.972G>C (p.Trp324Cys)

gnomAD frequency: 0.00003  dbSNP: rs758298916

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167906	SCV000218554	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 324 of the RET protein (p.Trp324Cys). This variant is present in population databases (rs758298916, gnomAD 0.06%). This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 11955539). ClinVar contains an entry for this variant (Variation ID: 188078). 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.
Counsyl	RCV000409785	SCV000490073	uncertain significance	Multiple endocrine neoplasia type 2B	2016-10-27	criteria provided, single submitter	clinical testing
Counsyl	RCV000410975	SCV000490074	uncertain significance	Multiple endocrine neoplasia type 2A	2016-10-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001107611	SCV001264777	likely benign	Multiple endocrine neoplasia	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001107612	SCV001264778	uncertain significance	Renal hypodysplasia/aplasia 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001107613	SCV001264779	uncertain significance	Hirschsprung disease, susceptibility to, 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001107614	SCV001264780	uncertain significance	Pheochromocytoma	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000994377	SCV001789602	uncertain significance	not provided	2024-06-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with Hirschsprung disease (PMID: 11955539); This variant is associated with the following publications: (PMID: 15956201, 16732321, 14633923, 11955539)
Ambry Genetics	RCV002381533	SCV002693395	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-03	criteria provided, single submitter	clinical testing	The p.W324C variant (also known as c.972G>C), located in coding exon 5 of the RET gene, results from a G to C substitution at nucleotide position 972. The tryptophan at codon 324 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in one individual from a cohort of 76 Caucasians from Germany with Hirschsprung’s disease (Fitze G et al. Lancet 2002 Apr; 359(9313):1200-5). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Based on the supporting evidence, the association of this alteration with Hirschsprung's disease is unknown; however, the association of this alteration with MEN2 is unlikely.
Myriad Genetics, Inc.	RCV000410975	SCV004018497	uncertain significance	Multiple endocrine neoplasia type 2A	2023-04-18	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV001107613	SCV005054177	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-03-13	criteria provided, single submitter	clinical testing