rs397514030

Variant names:

• chr5-112819342-CAAG-C
• rs397514030
• NM_000038.6:c.1311_1312+1delAAG

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS2 PS4 PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1311_1312+1del variant in APC occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of exon 10, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in a family with FAP and CHRPE (father [index] and two affected children), resulting in a total phenotype score of 1 (PS4_supporting). The variant occurred de novo in the index patient (paternity/ maternity confirmed; PS2). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS2, PS4_supporting and PM2_supporting (VCEP specifications version 1; date of approval: 10/12/22). LINK:https://erepo.genome.network/evrepo/ui/classification/CA251620/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.60

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 17 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS2: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1311_1312+1delAAG	p.Met438ProfsTer2406	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 10 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1311_1312+1delAAG	p.Met438ProfsTer2406	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 10 of 16	5	NM_000038.6	ENSP00000257430.4

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:2

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Pathogenic:2

Jan 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 19, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1311_1312+1del variant in APC occurs within the canonical splice donor site of intron 10. It is predicted to cause skipping of exon 10, resulting in a frameshift in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant has been reported in a family with FAP and CHRPE (father [index] and two affected children), resulting in a total phenotype score of 1 (PS4_supporting). The variant occurred de novo in the index patient (paternity/ maternity confirmed; PS2). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PVS1, PS2, PS4_supporting and PM2_supporting (VCEP specifications version 1; date of approval: 10/12/22). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.98		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.98		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514030; hg19: chr5-112155039;