APC p.Arg141Lys

The NM_000038.6(APC):c.422G>A (p.Arg141Lys) variant in APC is a G to non-G change at the last nucleotide of exon 4. It is predicted to cause skipping of exon 4, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (List B; PVS1_Strong). However, exon skipping could not be confirmed by RTPCRSeq data. Even though this could be based on technical limitations, the variant allele was present in 35% of normally spliced reads, so the splicing impact seems to be low (internal data Ambry Genetics). The total minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0004% (1/236810 alleles), which is lower than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP (HCCP VCEP) threshold of < 0.001% (0.00001) for PM2_Supporting if the allele count is ≤ 1 and therefore meets this criterion (PM2_Supporting). The variant has been reported in three individuals without a colorectal cancer/polyposis associated phenotype (one person fulfills 0.5 points as a “healthy individual,” for the other two not enough information is available; BS2 not met; internal data Ambry Genetics). In summary, this variant is a variant of uncertain significance (VUS) for autosomal-dominant inherited FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PVS1_Strong and PM2_Supporting (VCEP specifications version v2.1.0; date of approval 11/24/2023).