rs1554085450

chr5-112839602-A-ACT

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.4009_4010dup(p.Gln1338CysfsTer78) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.07

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 does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 428 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 5-112839602-A-ACT is Pathogenic according to our data. Variant chr5-112839602-A-ACT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 469945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.4009_4010dup	p.Gln1338CysfsTer78	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.4009_4010dup	p.Gln1338CysfsTer78	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 10, 2017

For these reasons, this variant has been classified as Pathogenic. This variant removes the final portion of the C-terminus of the APC protein, including the Basic domain, the EB1 binding site, and the HDLG binding site, which mediate interactions with the cytoskeleton (PMID: 15311282, 17293347). While this variant has not been reported in the literature, different truncations downstream of this variant, p.Asp1942Glufs*27 and p.Asp1979Thrfs*64, have been observed in individuals and families affected with familial adenomatous polyposis and are considered pathogenic (PMID: 20434453, 9824584, 15108286, 11001924). While functional studies have not been performed to directly test the effect of this variant on APC protein function, these observations suggest that deletion of the C-terminal portion of the APC protein is causative of disease. This sequence change inserts 2 nucleotides in exon 16 of the APC mRNA (c.4009_4010dupCT), causing a frameshift at codon 1338. This creates a premature translational stop signal in the last exon of the APC mRNA (p.Gln1338Cysfs*78). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 1507 amino acids of the APC protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

curation

Sema4, Sema4

Mar 12, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554085450; hg19: chr5-112175299;