Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000115119 | SCV000149028 | uncertain significance | not provided | 2015-06-23 | criteria provided, single submitter | clinical testing | This variant is denoted APC c.7088A>G at the cDNA level, p.Lys2363Arg (K2363R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Lys2363Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. APC Lys2363Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the basic domain and the Ser-rich region (Azzopardi 2008, 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 Lys2363Arg is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV003534344 | SCV000282811 | uncertain significance | Familial adenomatous polyposis 1 | 2023-12-25 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 2363 of the APC protein (p.Lys2363Arg). This variant is present in population databases (rs587779806, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 127317). 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. |
Ambry Genetics | RCV001026018 | SCV001188318 | likely benign | Hereditary cancer-predisposing syndrome | 2022-09-22 | 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. |