Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000236719 | SCV000292458 | uncertain significance | not provided | 2015-10-06 | criteria provided, single submitter | clinical testing | This variant is denoted APC c.3691C>T at the cDNA level, p.Leu1231Phe (L1231F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Leu1231Phe was not observed at a significant allele frequency in 1000 Genomes. Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. APC Leu1231Phe occurs at a position that is not conserved across species and is located in the region responsible for down-regulation through a process mediated by direct ubiquitination (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether APC Leu1231Phe is pathogenic or benign. We consider it to be a variant of uncertain significance. |
| Ambry Genetics | RCV001020894 | SCV001182437 | likely benign | Hereditary cancer-predisposing syndrome | 2021-03-17 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: 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. |
| Invitae | RCV003765467 | SCV002266251 | uncertain significance | Familial adenomatous polyposis 1 | 2024-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1231 of the APC protein (p.Leu1231Phe). This variant is present in population databases (rs573020080, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of familial adenomatous polyposis (Invitae). ClinVar contains an entry for this variant (Variation ID: 243108). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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. |