Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV003742597 | SCV000647220 | uncertain significance | Familial adenomatous polyposis 1 | 2020-05-13 | criteria provided, single submitter | clinical testing | In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a APC-related disease. This sequence change replaces glutamic acid with glutamine at codon 74 of the APC protein (p.Glu74Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant also falls at the last nucleotide of exon 3 of the APC coding sequence, which is part of the consensus splice site for this exon. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001290660 | SCV001478788 | uncertain significance | not specified | 2021-01-16 | criteria provided, single submitter | clinical testing | Variant summary: APC c.220G>C (p.Glu74Gln), located in the exonic splice region as the last nucleotide alteration of APC exon 3, results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.220G>C in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance based upon identical ascertainment criteria. Based on the evidence outlined above, the variant was classified as uncertain significance. |