rs377767428
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3
The NM_020975.6(RET):c.2647G>A(p.Ala883Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,696 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A883F) has been classified as Likely pathogenic.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2647G>A | p.Ala883Thr | missense_variant | 15/20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.2647G>A | p.Ala883Thr | missense_variant | 15/20 | 5 | NM_020975.6 | ENSP00000347942.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461696Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 727142
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia, type 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 31, 2021 | This sequence change replaces alanine with threonine at codon 883 of the RET protein (p.Ala883Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with medullary thyroid carcinoma (PMID: 15531548, 25440022, 28946813). ClinVar contains an entry for this variant (Variation ID: 24958). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on RET function (PMID: 21810974). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Ala883 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9294615, 10679286, 21186952, 25244518, 28323957). 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 | All of Us Research Program, National Institutes of Health | Mar 09, 2023 | This missense variant replaces alanine with threonine at codon 883 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 has reported that this variant has low transforming activity based on focal formation, soft-agar growth and growth rate assays in ex vivo cells (PMID: 21810974). This variant has been reported in four individuals from three families affected with medullary thyroid cancer that include two unrelated heterozygous carriers (PMID: 28946813, 29515777, 31510104) and two siblings from a consanguineous family who are homozygous for this variant (PMID: 15531548, 31510104). At least three heterozygous carriers from this consanguineous family who are older than the affected siblings are asymptomatic for thyroid-related disease (PMID: 15531548). This variant has not been identified 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2024 | The p.A883T variant (also known as c.2647G>A), located in coding exon 15 of the RET gene, results from a G to A substitution at nucleotide position 2647. The alanine at codon 883 is replaced by threonine, an amino acid with similar properties. This variant has been reported in the homozyous state in two brothers with medullary thyroid cancer (MTC) diagnosed in their fifties; however, four relatives who were heterozygous for the variant did not have MTC (Elisei R et al. J. Clin. Endocrinol. Metab. 2004 Nov;89:5823-7). Studies of familial MTC, as well as apparently sporadic MTC cases, have identified this variant (Romei C et al. Eur. J. Endocrinol. 2010 Aug;163:301-8; Romei C et al. Clin. Endocrinol. (Oxf). 2015 Jun;82:892-9; Lebeault M et al. Thyroid. 2017 12;27:1511-1522; Romei C et al. Oncotarget. 2018 Feb;9:9875-9884). In vitro assays analyzing the transforming activity of RET variants, found that this variant had an intermediate number of focus formation units, therefore described as having low or non-transforming potential (Cosci B et al. Endocr. Relat. Cancer. 2011 Oct;18:603-12). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at