rs397514030

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PVS1 PM2_Supporting PS2 PS4

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_001407446.1 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic reviewed by expert panel P:2
• Conservation: PhyloP100: 9.60
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• classic or attenuated familial adenomatous polyposis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• desmoid tumor

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
• familial adenomatous polyposis 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• gastric adenocarcinoma and proximal polyposis of the stomach

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• APC-related attenuated familial adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Turcot syndrome with polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Cenani-Lenz syndactyly syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407446.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	NM_000038.6	MANE Select	c.1311_1312+1delAAG	p.Met438ProfsTer2406	frameshift splice_donor splice_region intron	Exon 10 of 16	NP_000029.2
	APC	NM_001407446.1		c.1341_1342+1delAAG	p.Met448ProfsTer2424	frameshift splice_donor splice_region intron	Exon 9 of 16	NP_001394375.1
	APC	NM_001354896.2		c.1311_1312+1delAAG	p.Met438ProfsTer2424	frameshift splice_donor splice_region intron	Exon 10 of 17	NP_001341825.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	APC	ENST00000257430.9	TSL:5 MANE Select	c.1311_1312+1delAAG	p.Met438ProfsTer2406	frameshift splice_donor splice_region intron	Exon 10 of 16	ENSP00000257430.4
	APC	ENST00000508376.6	TSL:1	c.1311_1312+1delAAG	p.Met438ProfsTer2406	frameshift splice_donor splice_region intron	Exon 11 of 17	ENSP00000427089.2
	APC	ENST00000508624.5	TSL:1	n.*633_*634+1delAAG		splice_region non_coding_transcript_exon	Exon 11 of 17	ENSP00000424265.1

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
2	-	-	Familial adenomatous polyposis 1 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514030; hg19: chr5-112155039;