Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003336348 | SCV001400467 | uncertain significance | Familial adenomatous polyposis 1 | 2023-05-16 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Arg348*) in the APC gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and likely results in the loss of 47 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of familial adenomatous polyposis . However, this variant has been observed to co-occur in individuals with a different variant in APC, but the nomenclature of variant, phase and the significance of this finding is unclear. (PMID: 11754114, 12007223). ClinVar contains an entry for this variant (Variation ID: 955439). Studies have shown that this premature translational stop signal results in the activation of a cryptic splice site in exon 10. Also, it is associated with skipping of exon 10 and partial skipping of exon 10, but the resulting mRNA isoform(s) may be naturally occurring (external communication). 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 | RCV002393560 | SCV002706745 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-09-28 | criteria provided, single submitter | clinical testing | The p.R348* alteration (also known as c.1042C>T), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 1042. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration has been reported in two FAP cohorts, however both reported individuals were Israeli and it cannot be discerned if they are related (Davidson S et al. Hum Mutat, 2002 Jan;19:83-4; Gavert N et al. Hum Mutat, 2002 Jun;19:664). In one family, two siblings (one affected, one with unknown phenotype) also carried an unspecified deletion in APC in cis; this deletion was inherited from an affected parent who was demonstrated to be a mosaic carrier (Davidson S et al. Hum Mutat, 2002 Jan;19:83-4). In silico splice site analysis for this alteration is inconclusive, however, preliminary RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 47 amino acids (Ambry internal data). This deletion occurs in APC coding exon 9, and a different in-frame loss in this exon is described as a naturally occurring alternate isoform; loss-of-function alterations in the lost portion are associated with attenuated phenotype due, presumably, to at least partial functionality of this alternate isoform (Sieber OM et al. Gut, 2006 Oct;55:1440-8). A similar inference can be made for the in-frame event associated with p.R348* suggesting a mechanism for further attenuated or possible lack of phenotype. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |
| Myriad Genetics, |
RCV003336348 | SCV004043308 | pathogenic | Familial adenomatous polyposis 1 | 2023-04-28 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. |
| Laboratory for Genotyping Development, |
RCV003163774 | SCV002758045 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research |