Variant rs387906238 details in Genebe, Genetics Data Aggregator

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.Lys398fs) 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

Genomes: not found (cov: 32)

Consequence

APC
NM_000038.6 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.51

Variant links:

Genes affected

APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]

APC links:

APC (HGNC:):

APC links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-112819223-CAA-C is Pathogenic according to our data. Variant chr5-112819223-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 828.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112819223-CAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.1192_1193delAA	p.Lys398fs	frameshift_variant	10/16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1192_1193delAA	p.Lys398fs	frameshift_variant	10/16	5	NM_000038.6	ENSP00000257430.4		P25054-1

Frequencies

GnomAD3 genomes

Cov.:

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2023	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 28, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics and Genomics, Karolinska University Hospital	Aug 08, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 08, 2019	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) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	Feb 10, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 23, 2024	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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing