Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV001012986 | SCV001173516 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-12-30 | criteria provided, single submitter | clinical testing | The c.1744-4C>G intronic pathogenic mutation results from a C to G substitution 4 nucleotides upstream from coding exon 14 in the APC gene. This nucleotide position is poorly conserved in available vertebrate species. This alteration has been observed in at least one individual who has a personal and/or family history that is consistent with APC-associated disease (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Invitae | RCV003535791 | SCV004369317 | pathogenic | Familial adenomatous polyposis 1 | 2023-06-23 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 433625). This variant has been observed in individual(s) with APC-related conditions (Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 14 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. |
Department of Pathology and Laboratory Medicine, |
RCV000504229 | SCV000591087 | uncertain significance | Carcinoma of colon | no assertion criteria provided | clinical testing | The APC c.1744-4C>G variant was not identified in the literature nor was it identified in the ClinVar, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The variant was identified in the COGR database. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.1744-4C>G variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. In addition 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. |