Submissions for variant NM_020975.6(RET):c.1083C>A (p.Asn361Lys)

gnomAD frequency: 0.00003  dbSNP: rs770587835

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000663048	SCV000786098	uncertain significance	Multiple endocrine neoplasia type 2A	2018-02-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000823028	SCV000963866	uncertain significance	Multiple endocrine neoplasia, type 2	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 361 of the RET protein (p.Asn361Lys). This variant is present in population databases (rs770587835, gnomAD 0.004%). This missense change has been observed in individual(s) with Hirschsprung disease and/or osteosarcoma (PMID: 10790203, 32179705). ClinVar contains an entry for this variant (Variation ID: 548864). 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 tolerated. Experimental studies have shown that this missense change affects RET function (PMID: 12915470, 26517685). 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	RCV001017228	SCV001178273	likely benign	Hereditary cancer-predisposing syndrome	2024-10-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genetic Services Laboratory, University of Chicago	RCV001816663	SCV002066755	uncertain significance	not specified	2021-01-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RET gene demonstrated a sequence change, c.1083C>A, in exon 6 that results in an amino acid change, p.Asn361Lys. This sequence change has been described in the gnomAD database with a frequency of 0.005% in the European sub-population (dbSNP rs770587835). The p.Asn361Lys change has been reported in an individual with Hirschsprung disease (PMID: 10790203). Functional studies have demonstrated that RET protein folding and cellular localization is impacted in the presence of this sequence change (PMID: 12915470, 26517685). The p.Asn361Lys change affects a poorly conserved amino acid residue located in a domain of the RET protein that is known to be functional. The p.Asn361Lys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences, the clinical significance of the p.Asn361Lys change remains unknown at this time.
Sema4, Sema4	RCV001017228	SCV002529910	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-26	criteria provided, single submitter	curation
GeneDx	RCV002469239	SCV002765582	uncertain significance	not provided	2022-12-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies are inconclusive: abnormal protein folding and RET protein localization, but with ubiquitination levels close to wildtype (Kjaer et al., 2003; Jori et al., 2015); This variant is associated with the following publications: (PMID: 14633923, 12915470, 10790203, 26517685, 32179705)
PreventionGenetics, part of Exact Sciences	RCV004533456	SCV004119816	uncertain significance	RET-related disorder	2023-05-17	criteria provided, single submitter	clinical testing	The RET c.1083C>A variant is predicted to result in the amino acid substitution p.Asn361Lys. This variant has previously been reported in patients with variable and possibly RET-related phenotypes (including Hirschsprung, osteosarcoma, and Lynch syndrome), and some functional studies support its pathogenicity (Hofstra et al. 2000. PubMed ID: 10790203; Kjaer et al. 2003. PubMed ID: 12915470; Kovac et al. 2020. PubMed ID: 32179705; Jóri et al. 2015. PubMed ID: 26517685). This variant is reported in 0.0047% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-43604498-C-A) and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/548864/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV004568482	SCV005054212	uncertain significance	Hirschsprung disease, susceptibility to, 1	2024-01-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002469239	SCV005623055	uncertain significance	not provided	2024-07-24	criteria provided, single submitter	clinical testing