Submissions for variant NM_000038.6(APC):c.835-7T>G

dbSNP: rs1554079128

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002527170	SCV000954725	likely pathogenic	Familial adenomatous polyposis 1	2023-09-20	criteria provided, single submitter	clinical testing	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. Studies have shown that this variant results in altered splicing and introduces a premature termination codon (PMID: 18433509). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 433614). This variant has been observed in individuals with familial adenomatous polyposis (PMID: 18433509; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the APC gene. It does not directly change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV002527170	SCV004044649	likely pathogenic	Familial adenomatous polyposis 1	2023-04-27	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18433509, 20649969, Myriad internal data].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500835	SCV000591054	likely pathogenic	not provided		no assertion criteria provided	clinical testing	The APC c.835-7T>G variant was identified in 1 of 192 proband chromosomes (frequency 0.005) from individuals with familial adenomatous polyposis (FAP) (Kanter-Smoler 2008) and was also identified in the HGMD and the “InSIGHT Colon Cancer Databases”. The variant was not identified in dbSNP, Clinvitae database COSMIC, Zhejiang Colon Cancer Database (LOVD), ClinVar database, Clinvitae, GeneInsight-COGR databases, UMD, The NHLBI GO Exome Sequencing Project, the genome aggregation consortium (Feb 27, 2017), and the Exome Aggregation Consortium database (August 8, 2016). The variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing, with 4 of 5 different programs predicting the abolishment of the known splicing acceptor site at nucleotide position c.835, and 2 of 5 predicting the creation of a splicing acceptor site at the position of the variant, c.835-7. Additionally, Kanter-Smoler (2008) detected an aberrant APC polypeptide pattern produced by this variant in an RNA-based protein truncation test. The authors of this study suggest that this base substitution introduces a new splice acceptor site which is apparently preferred by the splicing machinery and results in the inclusion of the last six bases of intron 10 (alias exon 7) causing a frameshift, which alters the protein's amino acid sequence and results in a premature termination codon downstream. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.