Submissions for variant NM_000038.6(APC):c.4875del (p.Gln1625fs)

dbSNP: rs587779794

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115097	SCV000149006	pathogenic	not provided	2018-01-10	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in APC is denoted c.4875delA at the cDNA level and p.Gln1625HisfsX25 (Q1625HfsX25) at the protein level. The normal sequence, with the base that is deleted in brackets, is TGCA[delA]CCCCA. The deletion causes a frameshift which changes a Glutamine to a Histidine at codon 1625, and creates a premature stop codon at position 25 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. APC c.4875delA has been observed in at least one individual reporting a personal history of colon polyps (Susswein 2015). We consider this variant to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222394	SCV002500617	likely pathogenic	Familial multiple polyposis syndrome	2022-03-24	criteria provided, single submitter	clinical testing	Variant summary: APC c.4875delA (p.Gln1625HisfsX25) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251178 control chromosomes (gnomAD). c.4875delA has been reported in the literature in at least one individual affected with Breast cancer and Colon polyps (Susswein_2016). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002336249	SCV002637418	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	clinical testing	The c.4875delA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 4875, causing a translational frameshift with a predicted alternate stop codon (p.Q1625Hfs*25). This alteration occurs at the 3' terminus of theAPC gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature, the impacted region is critical for protein function and a significant portion of the protein is affected (Ambry internal data). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV003335100	SCV004044227	pathogenic	Familial adenomatous polyposis 1	2023-05-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Invitae	RCV003335100	SCV004292825	pathogenic	Familial adenomatous polyposis 1	2023-08-16	criteria provided, single submitter	clinical testing	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. For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 127299). This premature translational stop signal has been observed in individual(s) with clinical features of APC-related conditions (PMID: 26681312). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1625Hisfs*25) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1219 amino acid(s) of the APC protein.