rs2304793

Variant names:

• chr5-112766273-T-C
• rs2304793
• NM_000038.6:c.136-53T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000038.6(APC):​c.136-53T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0371 in 1,289,398 control chromosomes in the GnomAD database, including 2,123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (817 hom., cov: 32)
  • Exomes 𝑓: 0.032 (1306 hom.)
• Consequence: APC NM_000038.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 0.502
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 5-112766273-T-C is Benign according to our data. Variant chr5-112766273-T-C is described in ClinVar as Benign. ClinVar VariationId is 82873.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.136-53T>C		intron_variant	Intron 2 of 15	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.136-53T>C		intron_variant	Intron 2 of 15	5	NM_000038.6	ENSP00000257430.4

Frequencies

GnomAD3 genomes AF: 0.0725 AC: 11020 AN: 152104 Hom.: 817 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0411

Gnomad ASJ AF: 0.0325

Gnomad EAS AF: 0.137

Gnomad SAS AF: 0.0683

Gnomad FIN AF: 0.00584

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0206

Gnomad OTH AF: 0.0803

GnomAD4 exome AF: 0.0323 AC: 36771 AN: 1137176 Hom.: 1306 AF XY: 0.0326 AC XY: 18950 AN XY: 580898

African (AFR) AF: 0.191 AC: 5139 AN: 26854

American (AMR) AF: 0.0366 AC: 1597 AN: 43606

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 833 AN: 23998

East Asian (EAS) AF: 0.118 AC: 4494 AN: 37974

South Asian (SAS) AF: 0.0596 AC: 4704 AN: 78886

European-Finnish (FIN) AF: 0.00876 AC: 465 AN: 53108

Middle Eastern (MID) AF: 0.0585 AC: 235 AN: 4014

European-Non Finnish (NFE) AF: 0.0208 AC: 17073 AN: 819256

Other (OTH) AF: 0.0451 AC: 2231 AN: 49480

GnomAD4 genome AF: 0.0725 AC: 11030 AN: 152222 Hom.: 817 Cov.: 32 AF XY: 0.0723 AC XY: 5380 AN XY: 74432

African (AFR) AF: 0.183 AC: 7598 AN: 41522

American (AMR) AF: 0.0412 AC: 630 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0325 AC: 113 AN: 3472

East Asian (EAS) AF: 0.137 AC: 711 AN: 5192

South Asian (SAS) AF: 0.0681 AC: 329 AN: 4828

European-Finnish (FIN) AF: 0.00584 AC: 62 AN: 10612

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0206 AC: 1402 AN: 67984

Other (OTH) AF: 0.0795 AC: 168 AN: 2114

Alfa AF: 0.0441 Hom.: 402

Bravo AF: 0.0819

Asia WGS AF: 0.122 AC: 421 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

- -

Familial adenomatous polyposis 1 Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial colorectal cancer Other:1

-

Systems Biology Platform Zhejiang California International NanoSystems Institute

Significance: other

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		0.50
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2304793; hg19: chr5-112101970;