rs147863331

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000038.6(APC):c.1825G>A(p.Val609Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000159 in 1,614,140 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 0.00088 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 9.60

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:

ENSG00000258864 (HGNC:):

ENSG00000258864 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015657783).

BP6

Variant 5-112835032-G-A is Benign according to our data. Variant chr5-112835032-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=1, Benign=3}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00088 (134/152316) while in subpopulation AFR AF= 0.00313 (130/41574). AF 95% confidence interval is 0.00269. There are 0 homozygotes in gnomad4. There are 58 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 134 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.1825G>A	p.Val609Ile	missense_variant	15/16	ENST00000257430.9	NP_000029.2	P25054-1Q4LE70

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.1825G>A	p.Val609Ile	missense_variant	15/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.228+6060G>A		intron_variant		3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000259

AC:

AN:

251294

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000841

AC:

123

AN:

1461824

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00338

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000880

AC:

134

AN:

152316

Hom.:

Cov.:

AF XY:

0.000779

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00313

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000202

Hom.:

Bravo

AF:

0.00103

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000362

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	APC: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2021	This variant is associated with the following publications: (PMID: 23159591, 25980754, 22585170, 26802149, 27978560, 28135145, 28873162, 26667234) -

Familial adenomatous polyposis 1

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 22, 2023	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 07, 2018	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 03, 2020	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 19, 2018

Variant summary: APC c.1825G>A (p.Val609Ile) results in a conservative amino acid change located in the Armadillo of 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 0.0003 in 277028 control chromosomes. The observed variant frequency is approximately 4.19 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.1825G>A has been reported in the literature in individuals affected with colorectal cancer, Lynch syndrome, breast cancer, and other unspecified phenotypes (Kerr_2013, Liang_2016, Pearlman_2016, Yurgelun_2017, Yurgelun_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrences with other pathogenic variant(s) have been reported (TP53 c.742C>T, p.Arg248Trp; APC c.3927_3931delAAAGA, p.Glu1309fsX4, internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign. -

Carcinoma of colon

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The APC p.Val609Ile variant was identified in 5 of 8718 proband chromosomes (frequency: 0.0006) from individuals or families with colorectal cancer (Kerr 2012, Pearlman 2017, Yurgelun 2015, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs147863331) as "With other allele", ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and three other submitters; as uncertain significance by Counsyl), and in LOVD 3.0 (1x as VUS). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 83 of 277028 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 83 of 24034 chromosomes (freq: 0.003), while the variant was not observed in the Other, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant was identified in our laboratory with a co-occurring pathogenic APC variant (c.4391_4394del, p.Glu1464Valfs*8), increasing the likelihood that the p.Val609Ile variant does not have clinical significance. The p.Val609 residue is conserved across mammals and other organisms, and four out of five 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

.;D;D;T;T

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D;D;D

M_CAP

Benign

0.036

MetaRNN

Benign

0.016

T;T;T;T;T

MetaSVM

Uncertain

-0.0079

MutationAssessor

Uncertain

2.7

.;M;M;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.90

N;N;N;N;.

REVEL

Uncertain

0.38

Sift

Benign

0.034

D;D;D;D;.

Sift4G

Uncertain

0.0050

D;D;D;D;D

Polyphen

0.99

.;D;D;.;.

Vest4

0.67, 0.55

MVP

0.78

ClinPred

0.16

GERP RS

5.9

Varity_R

0.61

gMVP

0.53

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