Submissions for variant NM_020975.6(RET):c.977A>G (p.Gln326Arg)

gnomAD frequency: 0.00003  dbSNP: rs863224778

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199477	SCV000255060	uncertain significance	Multiple endocrine neoplasia, type 2	2022-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 326 of the RET protein (p.Gln326Arg). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 216731). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV000574518	SCV000674877	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-04	criteria provided, single submitter	clinical testing	The p.Q326R variant (also known as c.977A>G), located in coding exon 5 of the RET gene, results from an A to G substitution at nucleotide position 977. The glutamine at codon 326 is replaced by arginine, an amino acid with highly similar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One. 2018 Apr;13:e0194098). This amino acid position is poorly 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.
Counsyl	RCV000662571	SCV000785179	uncertain significance	Multiple endocrine neoplasia type 2A	2017-05-26	criteria provided, single submitter	clinical testing
GeneDx	RCV002284372	SCV002574291	uncertain significance	not provided	2022-03-14	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; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV002485323	SCV002790534	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-05-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662571	SCV004018489	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	RCV003462340	SCV004206707	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-06-30	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000199477	SCV004828265	uncertain significance	Multiple endocrine neoplasia, type 2	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 326 of the RET protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with cutaneous melanoma and at least two independent additional primary cancers (PMID: 29641532). This variant has been identified in 4/280482 chromosomes 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.