10-43112173-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM5
The NM_020975.6(RET):c.1597G>A(p.Gly533Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000356 in 1,574,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G533C) has been classified as Pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1597G>A | p.Gly533Ser | missense_variant | 8/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1597G>A | p.Gly533Ser | missense_variant | 8/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000854 AC: 13AN: 152238Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000437 AC: 8AN: 183154Hom.: 0 AF XY: 0.0000409 AC XY: 4AN XY: 97852
GnomAD4 exome AF: 0.0000302 AC: 43AN: 1422622Hom.: 0 Cov.: 32 AF XY: 0.0000256 AC XY: 18AN XY: 703916
GnomAD4 genome AF: 0.0000853 AC: 13AN: 152356Hom.: 0 Cov.: 34 AF XY: 0.000107 AC XY: 8AN XY: 74508
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 2A Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 10, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Feb 07, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 18, 2023 | 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. - |
Multiple endocrine neoplasia, type 2 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2023 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | 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). Functional studies have shown that this variant does not appear to result in increased RET phosphorylation (PMID: 26395553). To our knowledge, this variant has not been reported in individuals affected with MEN2A syndrome but has been reported in individuals affected with paraganglioma/pheochromocytoma (PMID: 22517557), or Hirschsprung disease (PMID: 17009072, 23084198, 26395553). 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. - |
Hirschsprung disease, susceptibility to, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 20, 2024 | - - |
Multiple endocrine neoplasia type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 10, 2015 | - - |
Pheochromocytoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Renal hypodysplasia/aplasia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Multiple endocrine neoplasia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2020 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at