Submissions for variant NM_000038.6(APC):c.1192_1193del (p.Lys398fs)

dbSNP: rs387906238

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159588	SCV000209568	pathogenic	not provided	2019-05-08	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 in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 20223039, 20222047, 22941256, 26681312, 29954149, 9603437)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000000871	SCV000827100	pathogenic	Familial adenomatous polyposis 1	2023-02-02	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 828). This premature translational stop signal has been observed in individual(s) with familial adenomatouspolyposis (PMID: 9603437). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys398Glufs*5) 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).
Ambry Genetics	RCV001010266	SCV001170436	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-23	criteria provided, single submitter	clinical testing	The c.1192_1193delAA pathogenic mutation, located in coding exon 9 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 1192 to 1193, causing a translational frameshift with a predicted alternate stop codon (p.K398Efs*5). This alteration has been reported in multiple individuals with a personal history consistent with a diagnosis of familial adenomatous polyposis (FAP) or attenuated FAP (Ambry internal data; Young J et al. Hum. Mutat., 1998;11:450-5; Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114;Crobach S et al. Fam. Cancer, 2012 Dec;11:671-3; D'Elia G et al. Genes (Basel), 2018 Jun;9:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000159588	SCV001450437	pathogenic	not provided	2019-08-08	criteria provided, single submitter	clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV001010266	SCV003933672	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-10	criteria provided, single submitter	curation	Data included in classification: More than 7 meioses reported from one family (Young et al., 1998) (PP1_str) Deletion is between codon 49 and codon 2645 (PVS1_vstr) 0 observations in gnomAD v2.1.1 (PM2_sup) Family cases in literature attained 1.5 phenotype points (D’Elia et al., 2018), (Crobach et al., 2012) (PS4_sup) Data not included in classification: (Middeldorp et al., 2010) De novo variant detected in branch family, no further information recorded regarding parental phenotype or colonoscopy.
Myriad Genetics, Inc.	RCV000000871	SCV004044744	pathogenic	Familial adenomatous polyposis 1	2023-04-28	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	RCV000159588	SCV005625533	pathogenic	not provided	2024-11-20	criteria provided, single submitter	clinical testing	The APC c.1192_1193del (p.Lys398Glufs*5) variant alters the translational reading frame of the APC mRNA and causes the premature termination of APC protein synthesis. This variant has been reported in the published literature in individuals with familial adenomatous polyposis (PMID: 29954149 (2018), 22941256 (2012), 20223039 (2005), 9603437 (1998)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000000871	SCV000021021	pathogenic	Familial adenomatous polyposis 1	1998-01-01	no assertion criteria provided	literature only