Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000220818 | SCV000273159 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2014-12-29 | criteria provided, single submitter | clinical testing | The c.1959-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 15 in the APC gene. This alteration was reported in an individual with an attenuated FAP phenotype and was demonstrated to result in use of a cryptic splice acceptor site, causing an in-frame deletion of the first four codons of exon 15 (Aretz S, Hum. Mutat. 2004 Nov; 24(5):370-80). 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. To date, this alteration has been detected with an allele frequency of approximately 0.005% (greater than 21000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native acceptor splice site. Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV003335236 | SCV002284067 | likely pathogenic | Familial adenomatous polyposis 1 | 2023-03-28 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in the activation of a cryptic splice site in 16 (Invitae). ClinVar contains an entry for this variant (Variation ID: 229816). Disruption of this splice site has been observed in individuals with familial adenomatous polyposis and attenuated familial adenomatous polyposis (PMID: 15459959, 20685668; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 15 of the APC gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in the loss of 4 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. |
| Myriad Genetics, |
RCV003335236 | SCV004044636 | likely pathogenic | Familial adenomatous polyposis 1 | 2023-05-03 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. |
| Baylor Genetics | RCV002518241 | SCV004200485 | likely pathogenic | Familial adenomatous polyposis 1 | 2021-05-06 | criteria provided, single submitter | clinical testing | |
| Department of Pathology and Laboratory Medicine, |
RCV000501512 | SCV000591103 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing |