Submissions for variant NM_000038.6(APC):c.1530dup (p.Gly511fs)

dbSNP: rs1554081749

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000663045	SCV000786090	likely pathogenic	Familial adenomatous polyposis 1	2018-02-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000663045	SCV001591086	pathogenic	Familial adenomatous polyposis 1	2024-08-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly511Trpfs*26) 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 variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 548863). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824861	SCV002074460	pathogenic	Familial multiple polyposis syndrome	2022-01-29	criteria provided, single submitter	clinical testing	Variant summary: APC c.1530dupT (p.Gly511TrpfsX26) 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 251276 control chromosomes. c.1530dupT has been reported in the literature among unequivocally pathogenic variants in at-least one individual affected with Familial Adenomatous Polyposis (example, Kerr_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV000663045	SCV004019569	pathogenic	Familial adenomatous polyposis 1	2023-02-13	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	RCV004026072	SCV005038046	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-11	criteria provided, single submitter	clinical testing	The c.1530dupT pathogenic mutation, located in coding exon 11 of the APC gene, results from a duplication of T at nucleotide position 1530, causing a translational frameshift with a predicted alternate stop codon (p.G511Wfs*26). In a large (n=1591) series of patients referred for APC testing, this alteration was detected in 1 individual (Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.