Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| ARUP Laboratories, |
RCV000507726 | SCV000602512 | pathogenic | not specified | 2016-10-20 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV003535804 | SCV002228174 | pathogenic | Familial adenomatous polyposis 1 | 2022-10-23 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 439408). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant is also known as c.657+1G>A. Disruption of this splice site has been observed in individuals with familial adenomatous polyposis (PMID: 8381580, 20333795, 20434453, 20685668, 31062380). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 8 of the APC gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). |
| Ambry Genetics | RCV002413392 | SCV002675334 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-12-22 | criteria provided, single submitter | clinical testing | The c.834+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 7 of the APC gene. This mutation has been seen in multiple FAP patients and families of various ethnicities and was demonstrated to result in an out-of-frame mRNA transcript (Olschwang S et al. Am. J. Hum. Genet.,1993 Feb;52:273-9; Castellsagué E et al. Gastroenterology, 2010 Aug;139:439-47, 447.e; Sheng JQ et al. World J. Gastroenterol., 2010 Mar;16:1522-6; Kim DW et al. Hum. Mutat., 2005 Sep;26:281; Rivera B et al. Ann. Oncol., 2011 Apr;22:903-9; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. |
| Department of Pathology and Laboratory Medicine, |
RCV001356878 | SCV001552153 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | APC, EXON07, c.834+1G>A, r.spl?, Heterozygous, PathogenicrnThe APC c.834+1G>A variant was identified in 8 of 980 proband chromosomes (frequency: 0.008) from Czech, Slovak, Chinese, Spanish, Korean and Japanese individuals or families with FAP (Stekrova 2007, Sheng 2010, Rivera 2011, Kim 2005, Garcia-Lozano 2005, Enomoto 2000, Miyaki 1994). Intrafamilial phenotypic variability was seen in 1 family with the variant (Garcia-Lozano 2005). The variant was identified in Insight Colon Cancer Gene Variant Database (8x), but was not identified dbSNP, ClinVar, Clinvitae, GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.834+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |