The NM_000038.6(APC):c.531+5_531+8del variant is located in intron 5 of the APC gene. RT-PCR demonstrated that this variant impacts splicing by skipping of exon 5 resulting in a premature stop codon (PS3_Moderate, PMID: 15459959). This variant is absent from gnomAD v.2.1.1 (PM2_Supporting). This variant has been reported in 5 probands meeting phenotypic criteria, resulting in a total phenotype score of 3.5 (PS4_Moderate; internal data Labcorp Genetics [formerly Invitae] and Institute of Human Genetics, Bonn, Germany, PMID: 15459959 and 20223039). The results from two in silico splicing predictors (SpliceAI and VarSeak) indicate that this variant may affect splicing by disrupting the donor splice site of intron 5 of APC (PP3). 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 VCEP: PS3_Moderate, PM2_Supporting, PP3, and PS4_Moderate (VCEP specifications version v2.1.0; date of approval 11/24/2023).