Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV003148797 | SCV003836614 | uncertain significance | Familial adenomatous polyposis 1 | 2023-02-26 | reviewed by expert panel | curation | The c.8514C>A variant in APC is a variant predicted to cause a premature stop codon at position 2838 (p.Tyr2838*) in exon 16, downstream of codon 2645. As a result, the PVS1 rule is not applicable. This variant has been reported in 2 probands meeting phenotype criteria, resulting in a total phenotype score of 2 (PS4_moderate, Ambry and Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this is a Variant of Unknown Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4_moderate and PM2_supporting. (VCEP specifications version 1; date of approval: 12/12/2022). |
| Ambry Genetics | RCV000570311 | SCV000675877 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-30 | criteria provided, single submitter | clinical testing | The p.Y2838* variant (also known as c.8514C>A), located in coding exon 15 of the APC gene, results from a C to A substitution at nucleotide position 8514. This changes the amino acid from a tyrosine to a stop codon within coding exon 15. 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 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of 0.001% (greater than 90000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. This substitution and subsequent stop codon occur at the 3' terminus of APC and impact only the last 6 amino acids of the protein. The exact functional impact of these altered amino acids is unknown at this time; however, structural analysis suggests this deletion removes a known motif (Thr2841-Ser2842-Val2843) needed for protein binding involved in regulation of protein function (Slep KC et al, PLoS ONE 2012; 7(11):e50097 ; Zhang Z et al, PLoS ONE 2011 ; 6(8):e23507). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV003148797 | SCV002305977 | uncertain significance | Familial adenomatous polyposis 1 | 2020-12-01 | criteria provided, single submitter | clinical testing | 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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 486740). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr2838*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 6 amino acid(s) of the APC protein. |