rs1554080698

chr5-112821929-CTG-Cchr5-112821929-CTG-CTGTG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000038.6(APC):c.1354_1355del(p.Val452SerfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,460,922 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A449A) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.93

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]

ACMG classification

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 5-112821929-CTG-C is Pathogenic according to our data. Variant chr5-112821929-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 537527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112821929-CTG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.1354_1355del	p.Val452SerfsTer7	frameshift_variant	11/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.1354_1355del	p.Val452SerfsTer7	frameshift_variant	11/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460922 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726804

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	May 01, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2018	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in APC are known to be pathogenic (PMID: 17963004, 20685668). This variant has been reported in several individuals affected with familial adenomatous polyposis (PMID: 15300853, 20685668, 23159591, 16134147). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val452Serfs*7) in the APC gene. It is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 09, 2022

The c.1354_1355delGT pathogenic mutation, located in coding exon 10 of the APC gene, results from a deletion of two nucleotides at nucleotide positions 1354 to 1355, causing a translational frameshift with a predicted alternate stop codon (p.V452Sfs*7). This alteration has been reported in multiple individuals with a diagnosis of familial adenomatous polyposis (FAP) (Cowie S et al. Hum. Mutat., 2004 Sep;24:261-71; Aceto G et al. Hum. Mutat., 2005 Oct;26:394; Lagarde A et al. J. Med. Genet., 2010 Oct;47:721-2; Kerr SE et al. J Mol Diagn, 2013 Jan;15:31-43). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with APC-related disease (Ambry internal data). 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554080698; hg19: chr5-112157626;