Submissions for variant NM_000038.6(APC):c.3183_3187del (p.Lys1061_Gln1062insTer)

dbSNP: rs587779352

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162768	SCV000213245	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-31	criteria provided, single submitter	clinical testing	The c.3183_3187delACAAA pathogenic mutation (also known as p.Q1062*), located in coding exon 15 of the APC gene, results from a deletion of 5 nucleotides at nucleotide positions 3183 to 3187. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This mutation has been identified in numerous individuals and families from a variety of ethnic backgrounds with classic familial adenomatous polyposis (FAP), including some individuals with extra colonic manifestations including desmoid tumors, gastrointestinal cancers, papillary thyroid cancer, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and epidermal cysts (Miyoshi Y et al. Proc. Natl. Acad. Sci. U.S.A. 1992 May;89:4452-6; Won YJ et al. J. Hum. Genet. 1999;44:103-8; González S et al. Cancer Genet. Cytogenet. 2005 Apr;158:70-4; Kim DW et al. Hum. Mutat. 2005 Sep;26:281; Friedl W & Aretz S. Hered. Cancer Clin. Pract. 2005 Sep;3:95-114; Plawski A & Slomski R. J. Appl. Genet. 2008;49:407-14; Fostira F et al. BMC Cancer. 2010 Jul;10:389; Rivera B et al. Ann. Oncol. 2011 Apr;22:903-9; Kerr SE et al. J. Mol. Diagn. 2013 Jan;15:31-43; Papp J et al. Fam. Cancer. 2016 Jan;15(1):85-97; Dahl NA et al. J. Pediatr. Hematol. Oncol. 2016 07;38(5):e154-7). Of note, this alteration is also described as a truncation at codon 1061 or codon 1060, and as c.3221_3225delACAAA in the literature. In addition to the clinical data 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.
Eurofins Ntd Llc (ga)	RCV000077987	SCV000226392	pathogenic	not provided	2013-08-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000144562	SCV000253730	pathogenic	Familial adenomatous polyposis 1	2025-02-02	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln1062*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1782 amino acid(s) of the APC protein. This variant is present in population databases (rs587779352, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with familial adenomatous polyposis (PMID: 1316610, 8162022, 15771908). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88913). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (internal data). 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. This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; internal data). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000077987	SCV000256968	pathogenic	not provided	2020-07-29	criteria provided, single submitter	clinical testing	PVS1, PS4_Mod, PP4
GeneDx	RCV000077987	SCV000293390	pathogenic	not provided	2022-04-13	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15024739, 1316610, 11106555, 20649969, 15951557, 8162051, 19029688, 20007843, 25248397, 28127413, 27143045, 30897307, 19531215, 31469036, 16088911, 11748858, 11933206, 9375853, 8381581, 10083733, 10363573, 12007223, 10646887, 9950360, 7833931, 8395941, 8730280, 8381579, 8544194, 8162022, 20223039, 8990002, 18433509, 14961559, 20333795, 26625971, 25832318, 28533537, 28331559, 28135145, 26840078, 28975465, 29351919, 22692730, 29753700, 31069152, 30720243, 31159747, 27000756, 26446593, 20924072, 16134147, 31504825, 31598872, 18629513)
Counsyl	RCV000144562	SCV000488338	pathogenic	Familial adenomatous polyposis 1	2016-03-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000077987	SCV000600078	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	The APC c.3183_3187del (p.Gln1062*) variant causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in affected individuals with familial adenomatous polyposis (FAP) (PMIDs: 1316610 (1992), 8381579 (1993), 23159591 (2013), 26446593 (2016), 26625971 (2016), and 35189564 (2022)), medulloblastoma (PMIDs: 29351919 (2018), 29753700 (2018), and 31504825 (2020)), papillary thyroid carcinoma (PMID: 31469036 (2019), and breast and/or ovarian cancer (PMID: 31159747 (2019)). This variant was also reported to segregate with disease and occurred as de novo in unrelated patients (PMID: 8381579 (1993)). The frequency of this variant in the general population, 0.0000089 (1/112982 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000502016	SCV000694026	pathogenic	Familial multiple polyposis syndrome	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: APC c.3183_3187delACAAA (p.Gln1062X) 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. The variant allele was found at a frequency of 4e-06 in 250490 control chromosomes (gnomAD). c.3183_3187delACAAA has been reported in the literature in multiple individuals affected with Familial Adenomatous Polyposis and colorectal cancer (Inra_2015, Miyoshi_1992, Papp_2016). These data indicate that the variant is very likely to be associated with disease. 11 ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
National Molecular Genetics Centre of Cancer Research, N.N. Alexandrov National Cancer Centre of Belarus	RCV000144562	SCV000778310	pathogenic	Familial adenomatous polyposis 1	2018-05-28	criteria provided, single submitter	clinical testing	This sequence change (c.3183_3187delACAAA) creates a stop codon (p.Gln1062*) in exon 16 of the APC mRNA.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000502016	SCV000781075	pathogenic	Familial multiple polyposis syndrome	2016-11-01	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000077987	SCV000821693	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variation is a deletion of five nucleotides at position 1062 of the APC protein, resulting in the formation of new stop codon. Thus, a premature protein. This results in premature termination of protein synthesis and inactivation of one allele. This particular mutation has been described in international literature in patients with Familial adenomatous polyposis (PMID: 1316610, PMID: 8162022, PMID: 15771908). This mutation has been described in the mutation database ClinVar (Variation ID: 55683).
Mendelics	RCV000144562	SCV000838100	pathogenic	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000722012	SCV000853185	pathogenic	Craniopharyngioma	2016-02-29	criteria provided, single submitter	clinical testing	This is a frameshift mutation in which 5 nucleotides are deleted between coding positions 3183 and 3187 and is predicted to shift the reading frame at codon 1061.
Color Diagnostics, LLC DBA Color Health	RCV000162768	SCV000905975	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 5 nucleotides 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 identified in 1/250490 chromosomes 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 Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000077987	SCV001446775	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000077987	SCV001450058	pathogenic	not provided	2019-05-06	criteria provided, single submitter	clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV000144562	SCV001499606	pathogenic	Familial adenomatous polyposis 1	2020-04-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000077987	SCV001500823	pathogenic	not provided	2024-12-01	criteria provided, single submitter	clinical testing	APC: PVS1, PM2, PS4:Moderate
Revvity Omics, Revvity	RCV000077987	SCV003815521	pathogenic	not provided	2023-12-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000144562	SCV004015214	pathogenic	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change results in a premature translational stop signal in the APC gene (p.Gln1062*). This variant has been observed in several individuals affected with familial adenomatous polyposis (PMID: 1316610, 8162022, 15771908). ClinVar contains an entry for this variant (Variation ID: 88913) with 21 submissions all of which describe this variant 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). Therefore, this variant has been classified as pathogenic.
Myriad Genetics, Inc.	RCV000144562	SCV004018789	pathogenic	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000077987	SCV004025049	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000144562	SCV004034115	pathogenic	Familial adenomatous polyposis 1	2023-07-01	criteria provided, single submitter	research
Baylor Genetics	RCV000144562	SCV004202210	pathogenic	Familial adenomatous polyposis 1	2023-07-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997058	SCV004839779	pathogenic	Classic or attenuated familial adenomatous polyposis	2023-06-15	criteria provided, single submitter	clinical testing	This variant creates a premature termination codon in the last exon. The transcribed mRNA is predicted to escape nonsense mediated decay and result in protein truncation. This prediction has not been confirmed by functional studies. This variant has been reported in multiple individuals with familial adenomatous polyposis (PMID: 9101302, 9375853, 9703421, 11677205, 23159591). This variant is absent from or rare in large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000077987	SCV005879611	pathogenic	not provided	2024-08-30	criteria provided, single submitter	clinical testing	The APC c.3183_3187del; p.Gln1062Ter variant (rs587779352) is reported in several individuals with familial adenomatous polyposis (Lee 2022, Miyoshi 1992, Papp 2016), and is reported in ClinVar (Variation ID: 88913). This variant is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Lee JK et al. Necessity of multiplex ligation probe amplification in genetic tests: Germline variant analysis of the APC gene in familial adenomatous polyposis patients. Cancer Genet. 2022 Apr;262-263:95-101. PMID: 35189564. Miyoshi Y et al. Germ-line mutations of the APC gene in 53 familial adenomatous polyposis patients. Proc Natl Acad Sci U S A. 1992 May 15;89(10):4452-6. PMID: 1316610. Papp J et al. Contribution of APC and MUTYH mutations to familial adenomatous polyposis susceptibility in Hungary. Fam Cancer. 2016 Jan;15(1):85-97. PMID: 26446593.
Pathway Genomics	RCV000144562	SCV000189853	pathogenic	Familial adenomatous polyposis 1	2014-07-24	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353466	SCV000591132	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Gln1062X variant has been described as a common hotspot mutation in the literature, with a founder effect in at least one population (from the Spanish Balearic Islands) (Fostira 2010, Gonzales 2005). In six studies it was identified in 36 of 4386 chromosomes (frequency: 0.008) from individuals or families with familial adenomatous polyposis or colorectal cancer (Aceto 2005, Fostira 2010, Gonzales 2005, Kerr 2012, Plawski 2008, Wallis 1999), and was absent in control chromosomes from these studies. The variant was also identified in several database searches, including: GeneInsight COGR (classified as pathogenic by a clinical laboratory), HGMD, UMD (208X as a “causal” variant), COSMIC, Clinvitae, InSiGHT Colon Cancer Database (191X), Zhejiang Colon Cancer Database, and the ClinVar Database (classified as pathogenic by Emory Genetics Laboratory, Pathway Genomics, and Ambry Genetics). The p.Gln1062X variant leads to a premature stop codon at position 1062, which is predicted to lead to 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. Notably, this variant occurs in the last exon of the gene and stop codon or nonsense mutations in this region may not be subjected to nonsense mediated RNA decay, although further study would be required to validate this hypothesis and it is currently not possible to determine whether or not this might influence the severity of the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077987	SCV001744538	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000077987	SCV001965512	pathogenic	not provided		no assertion criteria provided	clinical testing