5-112828942-A-G

Variant names:

• chr5-112828942-A-G
• rs529306174
• NM_000038.6:c.1713A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000038.6(APC):​c.1713A>G​(p.Ala571Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,626 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A571A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: APC NM_000038.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0250
• 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 5-112828942-A-G is Benign according to our data. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112828942-A-G is described in CliVar as Benign/Likely_benign. Clinvar id is 377490.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.025 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.1713A>G	p.Ala571Ala	synonymous_variant	Exon 14 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.1713A>G	p.Ala571Ala	synonymous_variant	Exon 14 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.198A>G		non_coding_transcript_exon_variant	Exon 3 of 8	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251354 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461288 Hom.: 1 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726962

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.000116 AC: 10 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111562

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.0000268 AC XY: 2 AN XY: 74494

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000240 AC: 1 AN: 41582

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.013250), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000533 Hom.: 0

Bravo AF: 0.0000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial adenomatous polyposis 1 Benign:3

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The APC p.Ala571Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was not identified in the literature, nor was it identified in dbSNP, the NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, UMD, the “InSiGHT Colon Cancer Database”, or the COSMIC database. This variant was identified by our laboratory in a patient with a co-occurring pathogenic MUTYH mutation in homozygous state, increasing the likelihood that the APC p.Ala571Ala variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. -

Mar 06, 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. -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

Aug 09, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2015

GeneDx

Significance: 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. -

Hereditary cancer-predisposing syndrome Benign:2

Apr 28, 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. -

Nov 15, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Classic or attenuated familial adenomatous polyposis Benign:1

Dec 18, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Nov 11, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	9.0
DANN	Benign	0.67
PhyloP100		-0.025
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs529306174; hg19: chr5-112164639;