Submissions for variant NM_020975.6(RET):c.2982A>C (p.Lys994Asn)

gnomAD frequency: 0.00001  dbSNP: rs199718928

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411986	SCV000489943	uncertain significance	Multiple endocrine neoplasia type 2B	2016-08-16	criteria provided, single submitter	clinical testing
Counsyl	RCV000409131	SCV000489944	uncertain significance	Multiple endocrine neoplasia type 2A	2016-08-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458385	SCV000543839	uncertain significance	Multiple endocrine neoplasia, type 2	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 994 of the RET protein (p.Lys994Asn). This variant is present in population databases (rs199718928, gnomAD 0.009%). This missense change has been observed in individual(s) with ependymoma (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 41843). 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.
Ambry Genetics	RCV000568654	SCV000674750	likely benign	Hereditary cancer-predisposing syndrome	2020-10-29	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.
Fulgent Genetics, Fulgent Genetics	RCV002477061	SCV000894531	uncertain significance	Hirschsprung disease, susceptibility to, 1; Multiple endocrine neoplasia type 2B; Pheochromocytoma; Familial medullary thyroid carcinoma; Multiple endocrine neoplasia type 2A	2022-05-25	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001104857	SCV001261752	uncertain significance	Multiple endocrine neoplasia	2019-01-11	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	RCV001104858	SCV001261753	uncertain significance	Renal hypodysplasia/aplasia 1	2019-01-11	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	RCV001104859	SCV001261754	uncertain significance	Pheochromocytoma	2019-01-11	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	RCV001104860	SCV001261755	uncertain significance	Hirschsprung disease, susceptibility to, 1	2019-01-11	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.
GeneDx	RCV000034775	SCV003798500	uncertain significance	not provided	2022-07-29	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ependymoma and atherosclerosis (Zhang et al., 2015, Johnston et al., 2012); This variant is associated with the following publications: (PMID: 27600092, 26580448, 24336963, 22703879, 14633923)
Baylor Genetics	RCV001104860	SCV004208667	uncertain significance	Hirschsprung disease, susceptibility to, 1	2023-10-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000458385	SCV004838706	uncertain significance	Multiple endocrine neoplasia, type 2	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 994 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 been reported in an individual affected with ependymoma (PMID: 26580448). This variant has been identified in 13/282886 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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034775	SCV000043480	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.