rs776615468
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_020975.6(RET):āc.3206G>Cā(p.Trp1069Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W1069C) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.3206G>C | p.Trp1069Ser | missense_variant | 20/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.3206G>C | p.Trp1069Ser | missense_variant | 20/20 | 5 | NM_020975.6 | P4 | |
RET | ENST00000615310.5 | c.*1376G>C | 3_prime_UTR_variant | 17/17 | 5 | ||||
RET | ENST00000683007.1 | n.4169G>C | non_coding_transcript_exon_variant | 16/16 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251482Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135916
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461864Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727232
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 1069 of the RET protein (p.Trp1069Ser). This variant is present in population databases (rs776615468, gnomAD 0.002%). 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: 220521). 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | May 04, 2023 | This missense variant replaces tryptophan with serine at codon 1069 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 3/251482 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 | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Dec 09, 2021 | The RET c.3206G>C (p.Trp1069Ser) missense change has a maximum subpopulation frequency of 0.0026% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/10-43623578-G-C). Five of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. To our knowledge, this variant has not been reported in the literature in individuals with multiple endocrine neoplasia type 2. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PP3. - |
Multiple endocrine neoplasia type 2B Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 13, 2016 | - - |
Hirschsprung disease, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 13, 2023 | - - |
Multiple endocrine neoplasia type 2A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 13, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 21, 2023 | The p.W1069S variant (also known as c.3206G>C), located in coding exon 20 of the RET gene, results from a G to C substitution at nucleotide position 3206. The tryptophan at codon 1069 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at