Submissions for variant NM_020975.6(RET):c.2931C>G (p.Ser977Arg)

gnomAD frequency: 0.00004  dbSNP: rs375414982

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198200	SCV000255051	uncertain significance	Multiple endocrine neoplasia, type 2	2025-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 977 of the RET protein (p.Ser977Arg). This variant is present in population databases (rs375414982, gnomAD 0.006%). 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: 216722). 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	RCV000662775	SCV000785576	uncertain significance	Multiple endocrine neoplasia type 2A	2017-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679738	SCV000807038	uncertain significance	not provided	2017-10-05	criteria provided, single submitter	clinical testing
Mendelics	RCV000662775	SCV000838407	uncertain significance	Multiple endocrine neoplasia type 2A	2018-07-02	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001017530	SCV001178620	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-12	criteria provided, single submitter	clinical testing	The p.S977R variant (also known as c.2931C>G), located in coding exon 17 of the RET gene, results from a C to G substitution at nucleotide position 2931. The serine at codon 977 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is 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 multiple endocrine neoplasia type 2 (MEN2) 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). This variant has been detected in multiple individuals with no reported features of RET-associated disease (Ambry internal data). Based on the supporting evidence, the association of this alteration with Hirschprung disease is unknown; however, the association of this alteration with MEN2 is unlikely.
Fulgent Genetics, Fulgent Genetics	RCV002492921	SCV002797545	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-01-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000679738	SCV003195174	uncertain significance	not provided	2024-02-11	criteria provided, single submitter	clinical testing	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: 25877891, 14633923)
Baylor Genetics	RCV003462337	SCV004206728	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-03-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000198200	SCV004838701	uncertain significance	Multiple endocrine neoplasia, type 2	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 977 of the RET protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 hereditary cancer in the literature. This variant has been identified in 7/251384 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679738	SCV005623096	uncertain significance	not provided	2024-11-18	criteria provided, single submitter	clinical testing	The RET c.2931C>G (p.Ser977Arg) variant, to the best of our knowledge, has not been reported in individuals with RET-related conditions in the published literature. The frequency of this variant in the general population, 0.000044 (5/113684 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.