The NM_000038.6(APC):c.531+5G>A variant in APC is an intronic variant which consists of a G>A nucleotide substitution at the +5 position of intron 5 of the APC gene. The results from in silico splicing predictors (SpliceAI and MaxEntScan) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been reported in 3 probands meeting 2 phenotype points (PS4_Moderate; PMID: 21813337, GeneDX internal cases). The variant has been reported in 3 additional probands with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria (PMID: 25980754, 26681312, Ambry internal case). This variant has similar in silico predictions compared to another splicing variant at that same nucleotide position (c.531+5G>C) (PMID: 12010888, 20223039, 19196998, ClinVar ID 279681), which has been classified as likely pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (PS1_Moderate). In summary, this variant meets the criteria to be classified as Likely Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis: criteria PS1_Moderate, PS4_Moderate, PM2_Supporting and PP3 applied (VCEP specifications v2.1.0; date of approval 11/24/2023).