rs148725540

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:22O:1

Conservation

PhyloP100: 5.16

Variant links:

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 links:

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ACMG classification

Classification made for transcript

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=9, not_provided=1, Benign=6, Uncertain_significance=2}. 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/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.3173A>G	p.Asp1058Gly	missense_variant	16/16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.3173A>G	p.Asp1058Gly	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.000552

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.000591

AC XY:

AN XY:

135440

show subpopulations

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.:

Cov.:

AF XY:

0.000997

AC XY:

725

AN XY:

727210

show subpopulations

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:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74504

show subpopulations

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.:

Bravo

AF:

0.000434

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000478

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:22Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:9

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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 â€šÃ„ÃºWith other alleleâ€šÃ„Ã¹, 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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 28, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	APC: BP2, BS1 -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Familial adenomatous polyposis 1

Uncertain:2Benign:3

Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 22, 2023	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]. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 16, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Nov 24, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 05, 2021	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. -

not specified

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 30, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2017	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. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 08, 2021	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. -

Hereditary cancer-predisposing syndrome

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	May 09, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 18, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2014	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. -

APC-Associated Polyposis Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

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

LIST_S2

Benign

0.75

T;.;T;T

M_CAP

Benign

0.053

MetaRNN

Benign

0.034

T;T;T;T

MetaSVM

Uncertain

0.081

MutationAssessor

Benign

0.90

.;L;L;.

MutationTaster

Benign

0.98

D;D;D

PrimateAI

Uncertain

0.59

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over