chr5-112842218-A-G

Variant names:

• chr5-112842218-A-G
• rs886059798
• NM_000038.6:c.6624A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6 BP7

The NM_000038.6(APC):​c.6624A>G​(p.Glu2208Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.63
• Publications: 0 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

ENSG00000258864 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 5-112842218-A-G is Benign according to our data. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420. Variant chr5-112842218-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 350420.
• BP7: Synonymous conserved (PhyloP=2.63 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.6624A>G	p.Glu2208Glu	synonymous_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.6624A>G	p.Glu2208Glu	synonymous_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+13246A>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461548 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727114

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111718

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial adenomatous polyposis 1 Benign:2

Apr 05, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Sep 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

APC-Associated Polyposis Disorders Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

May 30, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Nov 20, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	6.6
DANN	Benign	0.59
PhyloP100		2.6
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

Other links and lift over

dbSNP: rs886059798; hg19: chr5-112177915;