Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000115090 | SCV000148999 | uncertain significance | not provided | 2017-08-07 | criteria provided, single submitter | clinical testing | This variant is denoted APC c.4217A>G at the cDNA level, p.Gln1406Arg (Q1406R) at the protein level, and results in the change of a Glutamine to an Arginine (CAG>CGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC Gln1406Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. APC Gln1406Arg occurs at a position that is conserved in mammals and is located in the 20-amino acid repeat Beta-catenin down-regulating domain (Azzopardi 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Gln1406Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. |
Invitae | RCV002228226 | SCV000552683 | uncertain significance | Familial adenomatous polyposis 1 | 2023-11-10 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 1406 of the APC protein (p.Gln1406Arg). This variant is present in population databases (rs372241082, gnomAD 0.007%). 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: 127293). 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 | RCV000575175 | SCV000667278 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-25 | criteria provided, single submitter | clinical testing | The p.Q1406R variant (also known as c.4217A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4217. The glutamine at codon 1406 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Color Diagnostics, |
RCV000575175 | SCV000911960 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-04-05 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamine with arginine at codon 1406 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 3/251066 chromosomes 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. |