Submissions for variant NM_000038.6(APC):c.3901dup (p.Thr1301fs)

dbSNP: rs1554085382

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000657192	SCV000778915	pathogenic	not provided	2024-08-23	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9101302, 23085758, 23159591, 22864938)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222536	SCV002500144	pathogenic	Familial multiple polyposis syndrome	2024-09-19	criteria provided, single submitter	clinical testing	Variant summary: APC c.3901dupA (p.Thr1301AsnfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein, and at-least one downtream frameshifting variant has been evaluated PATH (c.4393_4394dupAG p.Ser1465ArgfsX9). The variant was absent in 250960 control chromosomes. c.3901dupA has been reported in the literature in at least one individual affected with Familial Adenomatous Polyposis (Gismondi_1997). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22864938, 9101302). ClinVar contains an entry for this variant (Variation ID: 433656). Based on the evidence outlined above, the variant was classified as pathogenic.
Sema4, Sema4	RCV002255418	SCV002536170	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002496933	SCV002812831	pathogenic	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2022-03-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004564239	SCV004044438	pathogenic	Familial adenomatous polyposis 1	2023-05-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Ambry Genetics	RCV002255418	SCV005459961	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-06	criteria provided, single submitter	clinical testing	The c.3901dupA variant, located in coding exon 15 of the APC gene, results from a duplication of A at nucleotide position 3901, causing a translational frameshift with a predicted alternate stop codon (p.T1301Nfs*14). This alteration occurs at the 3' terminus of the APC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 54% of the protein. However, premature stop codons are typically deleterious in nature. This variant has been reported in a familial adenomatous polyposis cohort Gismondi V et al. Hum Mutat, 1997;9:370-3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000502705	SCV000591158	pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Thr1301AsnfsX14 variant was identified in the literature as a somatic mutation in the tumour of a patient with sporadic colorectal cancer (Christie 2013). The variant was also identified in the HGMD, UMD (1X), the InSiGHT Colon Cancer database and the COSMIC database (2X). The p.Thr1301AsnfsX14 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1301 and leads to a premature stop codon 14 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 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.