chr5-112819223-CAA-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000038.6(APC):c.1192_1193delAA(p.Lys398GlufsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000038.6 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Pathogenic:3
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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). -
- -
not provided Pathogenic:3
- -
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) -
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. -
Hereditary cancer-predisposing syndrome Pathogenic:2
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. -
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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at