ClinVar Miner

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

dbSNP: rs1554086185
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Total submissions: 5
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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 2017-06-06 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 is expected to result in loss of function by premature protein truncation. As such, this alteration 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.

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