Submissions for variant NM_000038.6(APC):c.2083del (p.Gln695fs)

dbSNP: rs1554083941

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657449	SCV000779184	pathogenic	not provided	2018-10-08	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in APC is denoted c.2083delC at the cDNA level and p.Gln695ArgfsX23 (Q695RfsX23) at the protein level. The normal sequence, with the base that is deleted in brackets, is AGAC[delC]AGGA. The deletion causes a frameshift which changes a Glutamine to an Arginine at codon 695, and creates a premature stop codon at position 23 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature as a germline variant, it is predicted to cause loss of normal protein function through protein truncation as the last 2149 amino acids are lost and replaced with 22 incorrect amino acids. We consider this variant to be pathogenic.
Invitae	RCV003336125	SCV003451910	pathogenic	Familial adenomatous polyposis 1	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln695Argfs*23) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 2149 amino acid(s) of the APC protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 545865). 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. 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.
Myriad Genetics, Inc.	RCV003336125	SCV004045542	pathogenic	Familial adenomatous polyposis 1	2023-05-04	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.