Submissions for variant NM_000038.6(APC):c.233_236del (p.Asp78fs)

dbSNP: rs1064793020

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481173	SCV000564557	pathogenic	not provided	2022-06-17	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); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in the published literature (Spirio 1993); This variant is associated with the following publications: (PMID: 8252630)
Ambry Genetics	RCV000492026	SCV000579852	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-29	criteria provided, single submitter	clinical testing	The c.233_236delATAG pathogenic mutation, located in coding exon 3 of the APC gene, results from a deletion of 4 nucleotides at nucleotide positions 233 to 236, causing a translational frameshift with a predicted alternate stop codon (p.D78Afs*7). This mutation was identified in a kindred affected with attenuated FAP (Spirio L et al. Cell, 1993 Dec;75:951-7). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525748	SCV000647230	pathogenic	Familial adenomatous polyposis 1	2024-02-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp78Alafs*7) 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 attenuated familial adenomatous polyposis (AFAP) (PMID: 8252630). This variant is also known as c.232_235del4. ClinVar contains an entry for this variant (Variation ID: 418005). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001778973	SCV002014930	pathogenic	Familial multiple polyposis syndrome	2021-10-16	criteria provided, single submitter	clinical testing	Variant summary: APC c.233_236delATAG (p.Asp78AlafsX7) 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 251310 control chromosomes (gnomAD). c.233_236delATAG has been reported in the literature in individuals affected with attenuated form of Familial Adenomatous Polyposis (example, Spirio_1993, Wu_2001, Wang_2019). This variant is also known as c.232_235del4 and c.230_233_delTAGA in the literature (Spirio_1993, Wu_2001 and Wang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Myriad Genetics, Inc.	RCV002525748	SCV004043957	pathogenic	Familial adenomatous polyposis 1	2023-04-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
CeGaT Center for Human Genetics Tuebingen	RCV000481173	SCV004185292	pathogenic	not provided	2024-08-01	criteria provided, single submitter	clinical testing	APC: PP1:Strong, PVS1:Strong, PM2, PP4
PreventionGenetics, part of Exact Sciences	RCV003962330	SCV004782717	pathogenic	APC-related disorder	2023-11-09	no assertion criteria provided	clinical testing	The APC c.233_236delATAG variant is predicted to result in a frameshift and premature protein termination (p.Asp78Alafs*7). This variant has been reported in a family to be causative for attenuated adenomatous polyposis coli (Spirio et al. 1993. PubMed ID: 8252630, kindred 6). This variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/418005/?new_evidence=true). Frameshift variants in APC are expected to be pathogenic. This variant is interpreted as pathogenic.