rs863224286

Variant names:

• chr5-112780912-C-A
• rs863224286
• NM_000038.6:c.645+9C>A

Your query was ambiguous. Multiple possible variants found:

• chr5-112780912-C-A
• chr5-112780912-C-G
• chr5-112780912-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 1P and 3B. BP4 BP7 BS2_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.645+9C>A (p.?) variant in APC is an intronic variant at or beyond +7/–21 and is not predicted to impact splicing by multiple splicing predictors including SpliceAI, VarSEAK and MaxEntScan (BP4, BP7). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been observed in heterozygous state in 7 healthy unrelated adult individuals worth 6.5 (≥ 3) healthy individual points in total (BS2_Supporting; Ambry, Invitae internal data). In summary, this variant meets the criteria to be classified as Likely Benign 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, BP4, and BP7 (VCEP specifications version 1.0; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA337726/MONDO:0021056/089

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Likely benign reviewed by expert panel B:4
• Conservation: PhyloP100: -0.930

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 Likely_benign. Variant got -2 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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.645+9C>A		intron_variant	Intron 6 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.645+9C>A		intron_variant	Intron 6 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1411292 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 704618

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

Familial adenomatous polyposis 1 Benign:3

Feb 26, 2024

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 18, 2023

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.645+9C>A (p.?) variant in APC is an intronic variant at or beyond +7/-21 and is not predicted to impact splicing by multiple splicing predictors including SpliceAI, VarSEAK and MaxEntScan (BP4, BP7). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). This variant has been observed in heterozygous state in 7 healthy unrelated adult individuals worth 6.5 (more than 3) healthy individual points in total (BS2_Supporting; Ambry, Invitae internal data). In summary, this variant meets the criteria to be classified as Likely Benign 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, BP4, and BP7 (VCEP specifications version 1.0; date of approval: 12/12/2022). -

not specified Benign:1

Nov 01, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.3
DANN	Benign	0.87
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs863224286; hg19: chr5-112116609;