rs587776520

chr5-112841173-ATTCT-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000038.6(APC):c.5582_5585del(p.Ser1861Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D1860D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.45

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 16 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 157 pathogenic variants in the truncated region.
• PP5: Variant 5-112841173-ATTCT-A is Pathogenic according to our data. Variant chr5-112841173-ATTCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 821.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112841173-ATTCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.5582_5585del	p.Ser1861Ter	frameshift_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.5582_5585del	p.Ser1861Ter	frameshift_variant	16/16	5	NM_000038.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 17, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the APC protein in which other variant(s) (p.Tyr2645Lysfs*14) have been determined to be pathogenic (PMID: 1316610, 8381579, 9824584, 22135120, 27081525; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 821). This variant is also known as 1860delTTCT. This premature translational stop signal has been observed in individual(s) with attenuated familial adenomatous polyposis (PMID: 8931709, 17489848). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1861*) in the APC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 983 amino acid(s) of the APC protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 08, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1996	- -

Familial multiple polyposis syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 11, 2017

Variant summary: The APC c.5582_5585delCTTT (p.Ser1861fsX1) variant results in a termination codon in the last exon, however deletes a large number of amino acids (i.e. deletes the last 981 amino acids). Truncations downstream of this position have been classified as pathogenic/likely pathogenic by clinical laboratories in ClinVar (e.g. c.5952_5955delTG, c.5973delG, c.6053delC, etc.). This variant is absent in 245758 control chromosomes (gnomAD). This variant has been reported in a large Dutch family with attenuated familial adenomatous polyposis where it co-segregated with disease (van der Luijt_1996). Western blot analysis of lymphoblastoid cell lines derived from affected family members from this kindred showed only the wild-type APC protein, showing that it does not result into stable truncated APC protein. Multiple reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

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: rs587776520; hg19: chr5-112176870;