Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000568191 | SCV000667540 | uncertain significance | Hereditary cancer-predisposing syndrome | 2016-03-28 | criteria provided, single submitter | clinical testing | The c.220G>A variant (also known as p.E74K), located in coding exon 2 of the APC gene, results from a G to A substitution at nucleotide position 220. The amino acid change results in glutamic acid to lysine at codon 74, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 2, which makes it likely to have some effect on normal mRNA splicing. 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 6492 samples (12984 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 70000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV003767144 | SCV002237581 | uncertain significance | Familial adenomatous polyposis 1 | 2020-12-11 | criteria provided, single submitter | clinical testing | This variant has not been reported in the literature in individuals with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 482335). 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with lysine at codon 74 of the APC protein (p.Glu74Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. |