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

dbSNP: rs387906238

Total submissions: 7

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)
Invitae	RCV003534306	SCV000827100	pathogenic	Familial adenomatous polyposis 1	2023-02-02	criteria provided, single submitter	clinical testing	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). 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).
Ambry Genetics	RCV001010266	SCV001170436	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-19	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 (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:). 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.
OMIM	RCV000000871	SCV000021021	pathogenic	Familial adenomatous polyposis 1	1998-01-01	no assertion criteria provided	literature only