Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clinical Genetics and Genomics, |
RCV001270008 | SCV001450423 | pathogenic | not provided | 2019-05-07 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV000199388 | SCV002241289 | pathogenic | Familial adenomatous polyposis 1 | 2021-07-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 4, which introduces a premature termination codon (PMID: 15459959). The resulting mRNA is expected to undergo nonsense-mediated decay. 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: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 216017). This variant has been observed in individuals with features of familial adenomatous polyposis (PMID: 15459959, 17410430). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with serine at codon 141 of the APC protein (p.Arg141Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. |
| Center for Genomic Medicine, |
RCV001270008 | SCV002550562 | pathogenic | not provided | 2023-08-15 | criteria provided, single submitter | clinical testing | |
| Myriad Genetics, |
RCV000199388 | SCV004045547 | pathogenic | Familial adenomatous polyposis 1 | 2023-04-26 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15459959]. |
| Department of Pathology and Laboratory Medicine, |
RCV000501209 | SCV000591028 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The p.Arg141Ser variant was identified in 2 of 1834 proband chromosomes (frequency: 0.001) from individuals or families with Attenuated FAP (Aretz 2004). The variant was also identified the COSMIC database, InSiGHT Colon Cancer Gene Variant Database (4x as a splice mutation), and UMD (20x as a causal variant). In addition, functional analysis of the p.Arg141Ser variant has shown complete skipping of Exon 4 due to aberrant splicing (Aretz 2004, Kaufmann 2009). This variant was not identified in control databases: 1000 Genomes Project, Exome Variant Server project or the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015). A case study of a patient with the p.Arg141Ser variant and subsequent testing of her family has further confirmed an AFAP phenotype with this variant (Murphy 2007). The p.Arg141Ser variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. |