10-43120120-GC-TT
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PS1_ModeratePM1PM2PP3PP5_Very_Strong
The NM_020975.6(RET):c.2647_2648delinsTT(p.Ala883Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A883D) has been classified as Uncertain significance.
Frequency
Consequence
NM_020975.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.2647_2648delinsTT | p.Ala883Phe | missense_variant | 15/20 | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.2647_2648delinsTT | p.Ala883Phe | missense_variant | 15/20 | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Multiple endocrine neoplasia type 2B Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS) | May 21, 2023 | - - |
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Multiple endocrine neoplasia type 4 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Multiple endocrine neoplasia, type 1 Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Multiple endocrine neoplasia type 2A Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 13, 2016 | - - |
Multiple endocrine neoplasia, type 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 22, 2022 | Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This sequence change replaces alanine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 883 of the RET protein (p.Ala883Phe). This missense change has been observed in individual(s) with multiple endocrine neoplasia type 2 (PMID: 9294615, 25244518, 28323957). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RET function (PMID: 10679286). 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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available"). ClinVar contains an entry for this variant (Variation ID: 38629). - |
Medullary thyroid carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2023 | The c.2647_2648delGCinsTT pathogenic mutation (also known as p.A883F), located in coding exon 15 of the RET gene, results from an in-frame deletion of GC and insertion of TT at nucleotide positions 2647 to 2648. This results in the substitution of the alanine residue for a phenylalanine residue at codon 883, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals clinically diagnosed with MEN 2B with a personal and/or family history that is consistent with RET-related disease, and was reported as de novo in at least 2 unrelated probands (Smith DP et al. Oncogene, 1997 Sep;15:1213-7; Gimm O et al. J Clin Endocrinol Metab, 1997 Nov;82:3902-4; Jasim S et al. Thyroid, 2011 Feb;21:189-92; Mathiesen JS et al. Thyroid, 2015 Jan;25:139-40; Raue F et al. J Clin Endocrinol Metab, 2018 Jan;103:235-243; Fussey JM et al. Clin Endocrinol (Oxf), 2021 Aug;95:295-302). One functional study demonstrated high transforming activity without dimerization for p.A883F (Iwashita T et al. Oncogene, 1999 Jul;18:3919-22). Another study demonstrated that p.A883F exerted ligand-independent autophosphorylation and showed a sensitivity profile similar to known pathogenic RET alterations (Carlomagno F et al. Oncogene, 2004 Aug;23:6056-63). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at