Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000808449 | SCV000948558 | likely pathogenic | Familial adenomatous polyposis 1 | 2018-11-20 | criteria provided, single submitter | clinical testing | This variant occurs in a non-coding region of the APC gene. It does not change the encoded amino acid sequence of the APC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has been observed in an individual with clinical features consistent with familial adenomatous polyposis (Invitae). While experimental studies and prediction algorithms are not available for this variant, it disrupts a region of the APC promoter that has been proposed to include the DNA binding site for the YY1 transcription factor. Other variants that affect this region of the APC promoter (c.-30416G>A, c.-30417T>C, c.-30418A>G, and c.-30418A>T) have been shown to disrupt YY1 binding to the APC promoter and result in reduced APC expression (PMID: 20685668, 21813476, 27087319). Other variants that disrupt the DNA sequence in this region of the APC promoter have been observed in affected individuals (PMID: 20685668, 21813476, 27087319, 27343414, Invitae), suggesting that integrity of this region is clinically significant. As a result, variants that disrupt this region of the APC promoter are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Ambry Genetics | RCV002406810 | SCV002721424 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-21 | criteria provided, single submitter | clinical testing | The c.-192_-191delATinsTAGCAAGGG variant, located in in the 5' untranslated region (5’UTR) of the APC gene, results from the deletion of two nucleotides and the insertion of nine nucleotides at nucleotide positions -192 to -191 upstream of the first translated codon. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (Ambry internal data). Other alterations affecting these nucleotides (c.-192A>G, c.-191T>G, c.-191T>C) have been identified in GAPPS probands (Ambry internal data; Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42; Roberts AG et al. JPGN Reports, 2021 Nov;2(4):e123). This region has been identified as a highly conserved transcription factor binding site for the APC 1B promoter region and point mutations have been shown to disrupt transcriptional activity (Li J et al. Am. J. Hum. Genet. 2016 May;98:830-42). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |