rs1057517569

Positions:

• chr5-112842389-AACAGCCACCACTTCT-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BS2_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.6796_6810del variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 5 amino acids (p.Thr2266_Ser2270del). This variant has been observed in 3 heterozygous individuals over the age of 50 with no features of FAP or family history of FAP, which is worth 3 healthy individual points (BS2_Supporting; Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BS2_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA16042098/MONDO:0021056/089

• Frequency: Genomes: not found (cov: 32)
• Consequence: APC NM_000038.6 inframe_deletion
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 5.04

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6	c.6796_6810del	p.Thr2266_Ser2270del	inframe_deletion	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9	c.6796_6810del	p.Thr2266_Ser2270del	inframe_deletion	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: Uncertain significance

Submissions summary: Uncertain:5

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Mar 31, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 371858). This variant has not been reported in the literature in individuals affected with APC-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.6796_6810del, results in the deletion of 5 amino acid(s) of the APC protein (p.Thr2266_Ser2270del), but otherwise preserves the integrity of the reading frame. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2016	- -
Uncertain significance, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 26, 2023	The c.6796_6810del variant is predicted to cause a change in the length of the protein due to an in-frame deletion of 5 amino acids (p.Thr2266_Ser2270del). This variant has been observed in 3 heterozygous individuals over the age of 50 with no features of FAP or family history of FAP, which is worth 3 healthy individual points (BS2_Supporting; Invitae internal data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Due to insufficient evidence, this variant is classified as a Variant of Uncertain Significance (VUS) for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: BS2_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022). -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 14, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2023

The c.6796_6810del15 variant (also known as p.T2266_S2270del) is located in coding exon 15 of the APC gene. This variant results from an in-frame deletion of 15 nucleotides at nucleotide positions 6796 to 6810. This results in the in-frame deletion of 5 amino acids at codons 2266 to 2270. This amino acid region is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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: rs1057517569; hg19: chr5-112178086;