Submissions for variant NM_000038.6(APC):c.3202_3205del (p.Ser1068fs)

dbSNP: rs587779353

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130649	SCV000185529	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	The c.3202_3205delTCAA pathogenic mutation, located in coding exon 15 of the APC gene, results from the deletion of 4 nucleotides at positions 3202 to 3205, causing a translational frameshift with a predicted alternate stop codon (p.S1068Gfs*57). This mutation has been previously described in two unrelated probands. Eleven additional family members of one of the probands were also positive for the mutation, with clinical features including CHRPE, duodenal and gastric polyps, and epidermoid cysts (Paul P et al. Hum. Mol. Genet. 1993;2(7):925-31). In one meta analysis, this mutation was detected in 19/1164 German polyposis patients (Friedl W and Aretz S. Hered Cancer Clin Pract. 2005;3(3):95-114). In addition to the clinical information presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000206027	SCV000260417	pathogenic	Familial adenomatous polyposis 1	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ser1068Glyfs*57) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1776 amino acid(s) of the APC protein. This variant is present in population databases (rs587779353, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 8395941, 10646887, 19725996, 20333795, 23159591). It has also been observed to segregate with disease in related individuals. This variant is also known as 3202delTCAA or 3199_3202delCAAT. ClinVar contains an entry for this variant (Variation ID: 88914). 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.
GeneDx	RCV000201995	SCV000778914	pathogenic	not provided	2023-07-20	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 8395941, 18393237, 19029688, 28445943, 21476993, 10646887, 20685668, 9950360, 8187091, 10768871, 8162022, 16317745, 20223039, 8990002, 18433509, 14961559, 20333795, 20924072, 12357334, 23159591, 19725996, 20007843, 21779980, 19444466, 9101302, 26556299, 30720243, 31589614, 36225625)
Color Diagnostics, LLC DBA Color Health	RCV000130649	SCV001347422	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-08	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 16 of the APC gene, creating a frameshift and premature translation stop signal in the last coding exon. This mutant transcript is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the Beta-catenin binding domain, EB1 binding domain, HDLG binding domain, and NLS domains (PMID: 17881494). This variant has been reported in families affected with familial adenomatous polyposis (PMID:8395941, 10646887, 19725996, 20333795, 23159591, 20924072). This variant has been identified in 2/31408 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of APC function is a known mechanism of disease. Based on available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731359	SCV001983412	pathogenic	Familial multiple polyposis syndrome	2021-09-02	criteria provided, single submitter	clinical testing	Variant summary: APC c.3202_3205delTCAA (p.Ser1068GlyfsX57) 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 250414 control chromosomes (gnomAD). c.3202_3205delTCAA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis (e.g. Ficari_2000, Ripa_2002, Friedl_2005, Kerr_2013). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Laboratory of Molecular and Cellular Biology, University of Science and Technology Houari Boumediene	RCV000206027	SCV002102566	pathogenic	Familial adenomatous polyposis 1		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002228177	SCV004043955	pathogenic	Familial adenomatous polyposis 1	2023-05-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Baylor Genetics	RCV000206027	SCV004201535	pathogenic	Familial adenomatous polyposis 1	2023-07-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000201995	SCV000256969	pathogenic	not provided		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000501023	SCV000591134	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Ser1068GlyfsX57 variant was identified in 40 of 4390 proband chromosomes (frequency: 0.009) from individuals or families with familial adenomatous polyposis (De Rosa_2003_14961559, Enomoto_2000_10768871, Friedl_2005_20223039, Kanter-Smoler_2008_18433509, Paul_1993_8395941, Plawski_2008_19029688, Ripa_2002_12357334, Rivera_2011_20924072, Sheng_2010_20333795, van der Luijt_1997_8990002, Wallis_1999_9950360). The variant was also identified in dbSNP (ID: rs587779353) as “With Pathogenic allele”, ClinVar (as pathogenic by Ambry, Invitae, Mayo, and previously reported by Mount Sinai), Clinvitae (5x as pathogenic), Cosmic (in large intestine and soft tissue), LOVD 3.0 (75x), UMD-LSDB (56x as causal), and Zhejiang Colon Cancer Database (16x). The variant was not identified in the MutDB database. The variant was also identified by our laboratory in 3 individuals with familial adenomatous polyposis. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ser1068GlyfsX57 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1068 and leads to a premature stop codon at position 1124. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the APC gene are an established mechanism of disease in familial adenomatous polyposis and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.