Submissions for variant NM_000038.6(APC):c.3317del (p.Gly1106fs)

dbSNP: rs1561583917

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000772369	SCV000905547	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-02-17	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 16 of the APC gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 1 FAP family (PMID 10768871). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004561726	SCV002244764	pathogenic	Familial adenomatous polyposis 1	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly1106Glufs*20) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1738 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of familial adenomatous polyposis syndrome (PMID: 10634400). ClinVar contains an entry for this variant (Variation ID: 628070). This variant is expected to disrupt the EB1 and HDLG binding sites, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While functional studies have not been performed to directly test the effect on APC protein function, this suggests that disruption of the C-terminal portion of the protein is functionally important. A different truncation (p.Tyr2645Lysfs*14) that lies downstream of this variant has been determined to be pathogenic (PMID: 9824584, 1316610, 27081525, 8381579, 22135120, Invitae). This suggests that deletion of this region of the APC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.