Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000491162 | SCV000579873 | pathogenic | Hereditary cancer-predisposing syndrome | 2015-10-12 | criteria provided, single submitter | clinical testing | The p.R653G variant (also known as c.1957A>G), located in coding exon 14 of the APC gene, results from an A to G substitution at nucleotide position 1957, which is the next to last nucleotide of the exon. The arginine at codon 653 is replaced by glycine, an amino acid with dissimilar properties. This alteration, located in the Armadillo repeat domain of the APC gene, has been reported in an individual diagnosed with >100 adenomas at age 27y (Aretz S et al. Hum Mutat. 2004 Nov;24(5):370-80). In vitro and ex vivo splicing assays showed skipping of exon 14 which causes a major splicing defect (Aretz S et al. Hum Mutat. 2004 Nov;24(5):370-80; Grandval P et al. Hum Mutat. 2014 May;35(5):532-6). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6502 samples (13004 alleles) with coverage at this position. This nucleotide position is highly conserved in available vertebrate species. Using the ESEfinder splice site prediction tool, this alteration is prediced to weaken the efficiency of the native splice donor site. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Based on the available evidence, p.R653G is classified as a pathogenic mutation. |
| Invitae | RCV003535778 | SCV000821518 | pathogenic | Familial adenomatous polyposis 1 | 2023-10-03 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 653 of the APC protein (p.Arg653Gly). RNA analysis indicates that this missense change induces altered splicing and likely disrupts the C-terminus of the protein. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with familial adenomatous polyposis (PMID: 15459959, 19444466, 20223039, 26446593). ClinVar contains an entry for this variant (Variation ID: 428139). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Studies have shown that this missense change results in skipping of exon 15 and introduces a new termination codon (PMID: 15459959, 24599579). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Myriad Genetics, |
RCV002523967 | SCV004044712 | pathogenic | Familial adenomatous polyposis 1 | 2023-05-03 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 15459959]. |
| Department of Pathology and Laboratory Medicine, |
RCV001357824 | SCV001553411 | pathogenic | not provided | no assertion criteria provided | clinical testing |