Submissions for variant NM_000038.6(APC):c.147_150del (p.Lys49fs)

dbSNP: rs587781694

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129859	SCV000184676	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	The c.147_150delACAA pathogenic mutation, located in coding exon 2 of the APC gene, results from a deletion of 4 nucleotides between positions 147 and 150, causing a translational frameshift with a predicted alternate stop codon (p.K49Nfs*20). This mutation has been reported in multiple individuals with features of both familial adenomatous polyposis (FAP) and attenuated FAP (Gomez-Fernandez N et al. BMC Med. Genet. 2009 Jun 16;10:57; Rivera B et al. Ann. Oncol. 2011 Apr;22(4):903-9; Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. However, alterations that result in premature termination in coding exon 2 are associated with an attenuated phenotype and may have reduced penetrance compared to classic familial adenomatous polyposis syndrome. Clinical correlation is advised.
GeneDx	RCV000497263	SCV000209574	pathogenic	not provided	2022-10-21	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gmez-Fernndez et al., 2009; Rivera et al., 2011); 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26681312, 19531215, 20924072, 31285513)
Invitae	RCV003743586	SCV000647180	pathogenic	Familial adenomatous polyposis 1	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys49Asnfs*20) in the APC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with colon polyps, attenuated adenomatous polyposis (AFAP) and familial adenomatous polyposis (FAP) (PMID: 19531215, 20924072, 26681312). ClinVar contains an entry for this variant (Variation ID: 141368). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778749	SCV002014983	pathogenic	Familial multiple polyposis syndrome	2021-10-20	criteria provided, single submitter	clinical testing	Variant summary: APC c.147_150delACAA (p.Lys49AsnfsX20) 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 251042 control chromosomes (gnomAD). c.147_150delACAA has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Gomez-Fernandez_2009, Rivera_2011, Lorca_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000497263	SCV002774303	pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing	This frameshift variant causes the premature termination of APC protein synthesis. In addition, it has been reported in individuals with colon polyps, attenuated adenomatous polyposis (AFAP) and familial adenomatous polyposis (FAP) in the published literature (PMID: 19531215 (2009), 20924072 (2011), 23159591 (2013), 26681312 (2015), 31285513 (2019)). Therefore, the variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000552842	SCV004044759	pathogenic	Familial adenomatous polyposis 1	2023-04-24	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	RCV000552842	SCV004196478	pathogenic	Familial adenomatous polyposis 1	2023-10-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502854	SCV000591015	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Lys49AsnfsX20 variant was identified in 2 of 436 proband chromosomes (frequency: 0.005) from individuals or families with FAP (Gomez-Fernandez 2009, Rivera 2011). The variant was also identified in HGMD, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as a pathogenic variant by the Ambry Genetics), GeneInsight VariantWire database (1X, classified as “pathogenic” by a clinical laboratory), and UMD (12X).The p.Lys49AsnfsX20 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 49 and leads to a premature stop codon 20 codons downstream. 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. This alteration would typically be predicted to result in a truncated or absent protein and loss of function; however, one study has demonstrated that for APC mutations closer to the 5’ terminus, an internal ribosome entry site is utilized to initiate translation at codon 184, resulting in a partially functional N-terminally truncated protein, which results in an attenuated phenotype (Heppner Goss 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000552842	SCV000844923	pathogenic	Familial adenomatous polyposis 1	2018-06-01	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162574	SCV002758320	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research