Total submissions: 12
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000409959 | SCV000489747 | uncertain significance | Multiple endocrine neoplasia, type 2b | 2015-12-10 | criteria provided, single submitter | clinical testing | |
Counsyl | RCV000411509 | SCV000489748 | uncertain significance | Multiple endocrine neoplasia, type 2a | 2015-12-10 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000465806 | SCV000543800 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2024-02-01 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 533 of the RET protein (p.Gly533Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with Hirschsprung disease (PMID: 22517557, 23084198, 26395553). ClinVar contains an entry for this variant (Variation ID: 24887). 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. Experimental studies have shown that this missense change does not substantially affect RET function (PMID: 26395553). This variant disrupts the p.Gly533 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14602786, 16649977, 18805915, 22676047, 23461807). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 | RCV000573056 | SCV000674831 | likely benign | Hereditary cancer-predisposing syndrome | 2020-09-22 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
Mendelics | RCV000411509 | SCV001138025 | uncertain significance | Multiple endocrine neoplasia, type 2a | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Illumina Laboratory Services, |
RCV001102550 | SCV001259231 | uncertain significance | Hirschsprung disease, susceptibility to, 1 | 2017-04-27 | 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, |
RCV001102551 | SCV001259232 | uncertain significance | Pheochromocytoma | 2017-04-27 | 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, |
RCV001107801 | SCV001264979 | uncertain significance | Multiple endocrine neoplasia | 2017-04-27 | 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, |
RCV001107802 | SCV001264980 | uncertain significance | Renal hypodysplasia/aplasia 1 | 2017-04-27 | 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. |
St. |
RCV000411509 | SCV003843030 | uncertain significance | Multiple endocrine neoplasia, type 2a | 2023-02-07 | criteria provided, single submitter | clinical testing | The RET c.1597G>A (p.Gly533Ser) missense change has a maximum subpopulation frequency of 0.029% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, however functional studies performed on cell lines suggest that this variant does not affect RET function (PMID: 26395553). This variant has been reported in individuals with Hirshsprung disease (PMID: 17009072, 23084198, 26395553), hyperparathyroid disease (PMID: 32761341), and an individual with congenital anomalies of the kidney and urinary tract (PMID: 34979951). Other variant(s) that disrupt the p.Gly533 residue have been determined to be pathogenic (PMID: 14602786, 16649977, 22676047, 23461807). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance. |
Myriad Genetics, |
RCV000411509 | SCV004018077 | 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. |
Color Diagnostics, |
RCV000465806 | SCV004357233 | uncertain significance | Multiple endocrine neoplasia, type 2 | 2023-03-22 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with serine at codon 533 of the RET protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported that this variant does not impact RET function in RET and ERK phosphorylation (PMID: 2639553). This variant has been reported in at least one individual affected with paraganglioma or pheochromocytoma (PMID: 22517557). A different missense mutation at this codon, c.1597G>T (p.Gly533Cys), is reported as disease-causing in ClinVar (variation ID: 13950). This variant has been identified in 8/183154 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. |