rs148725540

Variant names:

• chr5-112838767-A-G
• rs148725540
• NM_000038.6:c.3173A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-112838767-A-G
• chr5-112838767-A-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000038.6(APC):​c.3173A>G​(p.Asp1058Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000988 in 1,614,178 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 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:24 O:1
• Conservation: PhyloP100: 5.16

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]

ENSG00000258864 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03436765).
• BP6: Variant 5-112838767-A-G is Benign according to our data. Variant chr5-112838767-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41523.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=10, Benign=7, Uncertain_significance=2, not_provided=1}. Variant chr5-112838767-A-G is described in Lovd as [Benign]. Variant chr5-112838767-A-G is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 85 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
APC	NM_000038.6	c.3173A>G	p.Asp1058Gly	missense_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.3173A>G	p.Asp1058Gly	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+9795A>G		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000599 AC: 150 AN: 250576 Hom.: 0 AF XY: 0.000591 AC XY: 80 AN XY: 135440

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00129

Gnomad NFE exome AF: 0.000743

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.00103 AC: 1510 AN: 1461820 Hom.: 0 Cov.: 33 AF XY: 0.000997 AC XY: 725 AN XY: 727210

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000730

Gnomad4 FIN exome AF: 0.00129

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000558 AC: 85 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74504

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000836 Hom.: 0

Bravo AF: 0.000434

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.000763

EpiControl AF: 0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:24 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:9

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 28, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

APC: BP2, BS1 -

-

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

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.Asp1058Gly variant was identified in 3 of 3262 proband chromosomes (frequency: 0.001) from individuals or families with gastric cancer or FAP (Ghatak 2017, Kerr 2013). The variant was also identified in dbSNP (ID: rs148725540) as “With other allele”, ClinVar (classified as benign by Ambry Genetics, Invitae; as likely benign by Color Genomics; as uncertain significance by Counsyl and one clinical laboratory), Clinvitae, Cosmic (2x in diffuse adenocarcinoma), MutDB, LOVD 3.0 (6x conflicting interpretations of pathogenicity), and in UMD-LSDB (6x likely neutral). In UMD the variant was identified with a co-occurring pathogenic APC variant (c.2016_2017delTA,p.His672GlnfsX7), increasing the likelihood that the p.Asp1058Gly variant does not have clinical significance. The variant was not identified in GeneInsight-COGR, or Zhejiang University databases. The variant was identified in control databases in 165 of 276366 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 9 of 24010 chromosomes (freq: 0.0004), Other in 1 of 6458 chromosomes (freq: 0.0002), Latino in 8 of 34390 chromosomes (freq: 0.0002), European in 93 of 126014 chromosomes (freq: 0.001), Finnish in 29 of 25782 chromosomes (freq: 0.001), and South Asian in 25 of 30766 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish, or East Asian, populations. The p.Asp1058 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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 likely benign. -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Familial adenomatous polyposis 1 Uncertain:2 Benign:3

Feb 16, 2018

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 22, 2023

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 24, 2015

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 05, 2021

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The APC c.3173A>G (p.Asp1058Gly) missense change has a maximum non-founder subpopulation frequency of 0.072% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112174464-A-G). This is higher than the reported incidence of APC-related familial adenomatous polyposis (BS1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in non-cancer control subjects and individuals without a phenotype suggestive of APC-related familial adenomatous polyposis (PMID: 30267214, internal data). This variant has been reported to co-occur with known pathogenic variants in APC (BP2; PMID: 23159591, UMD database). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP2. -

Hereditary cancer-predisposing syndrome Benign:5

May 09, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 21, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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. -

Mar 21, 2016

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 18, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Dec 16, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant NM_000038.6(APC):c.3173A>G (p.Asp1058Gly) has not been reported previously as a pathogenic variant, to our knowledge. . The p.Asp1058Gly variant is observed in 28/21,638 (0.1294%) alleles from individuals of gnomAD European Finnish background in gnomAD, which is greater than expected for the disorder. There is a moderate physicochemical difference between aspartic acid and glycine. The p.Asp1058Gly missense variant is predicted to be damaging by both SIFT and PolyPhen2. The nucleotide c.3173 in APC is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Benign. -

not specified Benign:4 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 08, 2021

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: APC c.3173A>G (p.Asp1058Gly) results in a non-conservative amino acid change located in the Adenomatous polyposis coli (APC) family (IPR026818) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 250576 control chromosomes, predominantly at a frequency of 0.00074 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 10 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3173A>G has been reported in the literature in individuals affected with Familial Adenomatous Polyposis, colorectal cancer, as well as unaffected individuals, without strong evidence for causality (e.g. Kerr_2013, Out_2015, Ghatak_2017, Johnston_2012). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrences with other pathogenic variants has been reported (APC c.2016_2017delTA, p.His672GlnfsX7, UMD; unspecified variants, Kerr_2013), providing supporting evidence for a benign role. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=6), variant of uncertain significance (n=3) and benign (n=2). Based on the evidence outlined above, the variant was classified as benign. -

Dec 19, 2017

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. -

Sep 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

APC-Associated Polyposis Disorders Benign:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Classic or attenuated familial adenomatous polyposis Benign:1

Sep 23, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer Benign:1

Jan 23, 2024

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	.;D;D;T
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.75	T;.;T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Uncertain	0.081	D
MutationAssessor	Benign	0.90	.;L;L;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.026	D;D;D;T
Polyphen		0.38	.;B;B;.
Vest4		0.53, 0.55
MVP		0.91
ClinPred		0.033	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.49

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: rs148725540; hg19: chr5-112174464; COSMIC: COSV57383428; COSMIC: COSV57383428;