Submissions for variant NM_000038.6(APC):c.646-8T>A

gnomAD frequency: 0.00001  dbSNP: rs879254149

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236430	SCV000293652	uncertain significance	not specified	2017-04-18	criteria provided, single submitter	clinical testing	This variant is denoted APC c.646-8T>A or IVS6-8T>A and consists of a T>A nucleotide substitution at the -8 position of intron 6 of the APC gene. Multiple in silico models predict this variant to weaken the nearby natural acceptor site, and to possibly cause abnormal gene splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. APC c.646-8T>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The thymine (T) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether APC c.646-8T>A is pathogenic or benign.
Invitae	RCV002518445	SCV000562608	likely benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771392	SCV000903731	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	This variant causes a T to A nucleotide substitution at the -8 position of intron 6 of the APC gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with colorectal cancer (PMID: 28135145). This variant has been identified in 1/31380 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236430	SCV001338604	uncertain significance	not specified	2020-04-23	criteria provided, single submitter	clinical testing	Variant summary: APC c.646-8T>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249338 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.646-8T>A has been reported in the literature in at least one individual affected with colorectal cancer (e.g. Yurgelun_2017). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. These laboratories cited the variant as likely benign (n=1) and uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.