Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV002514127 | SCV003441615 | pathogenic | Multiple endocrine neoplasia, type 2 | 2022-06-22 | criteria provided, single submitter | clinical testing | 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). |
Laboratory of Molecular and Cytogenetics, |
RCV000021873 | SCV003930403 | likely pathogenic | Multiple endocrine neoplasia, type 2b | 2023-05-21 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003298037 | SCV004009439 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-04-05 | criteria provided, single submitter | clinical testing | 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. |
Database of Curated Mutations |
RCV000422001 | SCV000504814 | likely pathogenic | Medullary thyroid carcinoma | 2015-07-14 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433892 | SCV000510497 | likely pathogenic | Multiple endocrine neoplasia, type 2a | 2016-05-13 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445104 | SCV000510498 | likely pathogenic | Multiple endocrine neoplasia type 4 | 2016-05-13 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426500 | SCV000510499 | likely pathogenic | Multiple endocrine neoplasia, type 1 | 2016-05-13 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000021873 | SCV000510501 | likely pathogenic | Multiple endocrine neoplasia, type 2b | 2016-05-13 | no assertion criteria provided | literature only |