The NM_000038.6(APC):c.7489dup (p.Ser2497PhefsTer14) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236770 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). This variant has been reported in 1 family meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, Invitae internal data). Moreover, the variant has been reported in one additional proband with a colorectal cancer/polyposis associated phenotype not meeting phenotypic criteria and in three unaffected individuals with a family history of gastrointestinal cancer and/or colorectal polyps (Ambry Genetics and Invitae internal data). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen HCCP VCEP: criteria PVS1, PS4_Supporting and PM2_Supporting applied (VCEP specifications version v2.0.3; date of approval 7/24/2023).