5-112780865-C-G

Position:

chr5-112780865-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1BP4_StrongBP6BS2

The NM_000038.6(APC):c.607C>G(p.Gln203Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000331 in 1,612,790 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 0.00033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00033 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:16O:2

Conservation

PhyloP100: 7.29

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 -7 ACMG points.

PM1

In a coiled_coil_region (size 121) in uniprot entity APC_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_000038.6

BP4

Computational evidence support a benign effect (MetaRNN=0.009639204).

BP6

Variant 5-112780865-C-G is Benign according to our data. Variant chr5-112780865-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41509.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, not_provided=2, Benign=7, Uncertain_significance=3}. Variant chr5-112780865-C-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 50 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.607C>G	p.Gln203Glu	missense_variant	6/16	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.607C>G	p.Gln203Glu	missense_variant	6/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.000329

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.0110

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000603

AC:

151

AN:

250412

Hom.:

AF XY:

0.000598

AC XY:

AN XY:

135360

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0124

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000331

AC:

484

AN:

1460680

Hom.:

Cov.:

AF XY:

0.000352

AC XY:

256

AN XY:

726642

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000981

Gnomad4 OTH exome

AF:

0.00104

GnomAD4 genome

AF:

0.000329

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.0110

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000946

Hom.:

Bravo

AF:

0.000359

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000494

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:16Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	APC: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2023	- -
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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 19, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 28, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jan 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 19, 2015	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 27, 2020	- -

not specified

Uncertain:1Benign:3Other:1

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in 1.2% of Ashkenazi Jewish alleles in gnomAD (121/10150). Frequency too high for disease. It is classified in ClinVar with 1 star as Likely benign/benign by Invitae and Ambry and as VUS by GeneDx and Biesecker lab. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 14, 2022	Variant summary: APC c.607C>G (p.Gln203Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251556 control chromosomes (gnomAD). The observed variant frequency is approximately 9 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 benign. c.607C>G has been reported in the literature in individuals affected with adrenocortical carcinoma and ependymoma (example, Zhang_2015), endometrial cancer (example, Kogan_2018), and male breast cancer (example, Rizzolo_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (BRCA1 c.68_69delAG, p.Glu23ValfsX17) providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple other ClinVar submitters (evaluation after 2014) cite the variant with a predominant consensus as as likely benign/benign (n=11) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 31, 2018	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. -

Familial adenomatous polyposis 1

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Gln203Glu variant was identified in the literature in 5 of 2506 control chromosomes (frequency: 0.002) from individuals with no personal or family history of cancer (Johnston 2012, Bodian 2014). The variant was also identified in dbSNP (ID: rs141576417) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics and GeneDx; as likely benign by Prevention Genetics, Color, and three other submitters; and as uncertain significance by one submitter), UMD (4x as "unclassified variant"), and LOVD 3.0 (1x). The variant was identified in control databases in 155 of 276178 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 129 of 10142 chromosomes (freq: 0.01), Other in 5 of 6448 chromosomes (freq: 0.0008), European in 18 of 126044 chromosomes (freq: 0.0001), and African in 3 of 24000 chromosomes (freq: 0.0001); it was not observed in the East Asian, Finnish, Latino, or South Asian populations. The p.Gln203 residue is conserved across mammals and other organisms and 4 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

APC-Associated Polyposis Disorders

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 29, 2019

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Familial multiple polyposis syndrome

Benign:1

Likely benign, criteria provided, single submitter

research

University of Washington Department of Laboratory Medicine, University of Washington

May 29, 2018

The APC variant designated as NM_000038.5:c.607C>G (p.Gln203Glu) is classified as likely benign. This variant is found in approximately 1 out of 500 individuals of European ancestry (exac.broadinstitute.org), which is a higher frequency than expected of a pathogenic APC variant (Kobayashi et al, 2017, PMID:28166811). It is listed in the ClinVar database (Variation ID: 41509) and has been classified as benign or likely benign by 7 clinical laboratories. In one obseved family, this variant was identified in two members who have been documented to have fewer than 5 colon polyps on colonoscopy. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter APC function or modify cancer risk. A modest (less than 2-fold) increase in risk of cancer or colon polyps due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. -

Desmoid disease, hereditary;C2713442:Familial adenomatous polyposis 1

Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.027

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

.;T;T;T

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

D;.;D;D

M_CAP

Benign

0.042

MetaRNN

Benign

0.0096

T;T;T;T

MetaSVM

Uncertain

-0.024

MutationAssessor

Benign

0.69

.;N;N;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.48

Sift

Uncertain

0.0080

D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.95

.;P;P;.

Vest4

0.61, 0.65

MVP

0.88

ClinPred

0.086

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.37

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