rs587781267

Positions:

chr5-112827916-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BS2BP4BS1BS3

This summary comes from the ClinGen Evidence Repository: The c.1549-13A>T variant in APC is an intronic variant which is located 13 nucleotides upstream of exon 13. This variant has been observed in 10 individuals worth 10 healthy individual points (Ambry internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.003915% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold (0.001%) for BS1, and therefore meets this criterion (BS1). RT-PCR demonstrated no impact of the variant on splicing with evidence of biallelic expression (BS3, Ambry internal data). The results from ≥2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) support that this variant does not affect splicing (BP4). In summary, this variant is classified as Benign for autosomal dominant familial adenomatous polyposis as specified by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP. Criteria applied: BS1, BS2, BS3, BP4 (Specification Version 1.0, date of approval: 10/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA005295/MONDO:0021056/089

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

APC
NM_000038.6 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign reviewed by expert panel U:1B:7

Conservation

PhyloP100: -1.46

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

For more information check the summary or visit ClinGen Evidence Repository.

BS1

For more information check the summary or visit ClinGen Evidence Repository.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

BS3

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.1549-13A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1549-13A>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

250586

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135426

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1457924

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

725606

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000261

Gnomad4 OTH exome

AF:

0.0000664

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152246

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Benign:3

Benign, reviewed by expert panel	curation	ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	Feb 19, 2023	The c.1549-13A>T variant in APC is an intronic variant which is located 13 nucleotides upstream of exon 13. This variant has been observed in 10 individuals worth 10 healthy individual points (Ambry internal data). The highest population minor allele frequency in the non-cancer cohort of gnomAD v2.1.1 is 0.003915% in the non-Finnish European population, which is higher than the ClinGen APC VCEP threshold (0.001%) for BS1, and therefore meets this criterion (BS1). RT-PCR demonstrated no impact of the variant on splicing with evidence of biallelic expression (BS3, Ambry internal data). The results from more than 2 in silico splicing predictors (SpliceAI, MaxEntScan, VarSeak) support that this variant does not affect splicing (BP4). In summary, this variant is classified as Benign for autosomal dominant familial adenomatous polyposis as specified by the InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP. Criteria applied: BS1, BS2, BS3, BP4 (Specification Version 1.0, date of approval: 10/12/2022). -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2024	This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 06, 2015	In silico models in agreement (benign);Other data supporting benign classification -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 22, 2017	- -

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 24, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Classic or attenuated familial adenomatous polyposis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 01, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.015

DANN

Benign

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over