Submissions for variant NM_000038.6(APC):c.4778del (p.Lys1593fs)

dbSNP: rs1554086185

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV003148798	SCV003836605	pathogenic	Familial adenomatous polyposis 1	2023-02-26	reviewed by expert panel	curation	The c.4778del p.(Lys1593Serfs*57) variant in APC is a frameshift variant located between codon 49 and 2645 and predicted to cause a premature stop codon in exon 16 in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in 2 probands meeting phenotypic criteria, resulting in a total phenotype score of 1 (PS4_Supporting, Internal lab contributors). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS4_Supporting, PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
Ambry Genetics	RCV000575274	SCV000675941	pathogenic	Hereditary cancer-predisposing syndrome	2024-06-11	criteria provided, single submitter	clinical testing	The c.4778delA pathogenic mutation, located in coding exon 15 of the APC gene, results from a deletion of one nucleotide at nucleotide position 4778, causing a translational frameshift with a predicted alternate stop codon (p.K1593Sfs*57). This alteration occurs at the 3' terminus of theAPC gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 47% of the protein. However, premature stop codons are typically deleterious in nature, and a significant portion of the protein is affected (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
GeneDx	RCV000657448	SCV000779183	pathogenic	not provided	2018-01-11	criteria provided, single submitter	clinical testing	This deletion of one nucleotide in APC is denoted c.4778delA at the cDNA level and p.Lys1593SerfsX57 (K1593SfsX57) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAAAAA[delA]GCCA. The deletion causes a frameshift which changes a Lysine to a Serine at codon 1593, and creates a premature stop codon at position 57 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic.
Myriad Genetics, Inc.	RCV003148798	SCV004045076	pathogenic	Familial adenomatous polyposis 1	2023-05-11	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657448	SCV004219466	pathogenic	not provided	2023-05-07	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the APC mRNA and causes the premature termination of APC protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). To the best of our knowledge, the variant has not been reported in the published literature. Based on the available information, this variant is classified as pathogenic.