5-112843215-A-G

Position:

chr5-112843215-A-G

Variant summary

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

The NM_000038.6(APC):c.7621A>G(p.Ile2541Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000899 in 1,613,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:5O:1

Conservation

PhyloP100: 1.45

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.066997826).

BP6

Variant 5-112843215-A-G is Benign according to our data. Variant chr5-112843215-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133514.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=1, not_provided=1, Uncertain_significance=4}. Variant chr5-112843215-A-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.7621A>G	p.Ile2541Val	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.7621A>G	p.Ile2541Val	missense_variant	16/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250678

Hom.:

AF XY:

0.0000960

AC XY:

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000196

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.0000876

AC:

128

AN:

1461532

Hom.:

Cov.:

AF XY:

0.0000811

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000935

Gnomad4 OTH exome

AF:

0.000132

GnomAD4 genome

AF:

0.000112

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000918

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000576

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:5Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Ile2541Val variant was identified in 1 of 1382 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal adenomas and was present in 1 of 3300 control chromosomes (frequency: 0.0003) from healthy individuals (Azzopardi 2008, Bodian 2014). The variant was also identified in dbSNP (ID: rs587778033) as "With Uncertain significance allele", ClinVar (classified as likely benign by Color and Ambry Genetics; as uncertain significance by Invitae, GeneDx and three other submitters), and UMD-LSDB (2x as neutral). The variant was not identified in LOVD 3.0 . The variant was identified in control databases in 26 of 276400 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24028 chromosomes (freq: 0.0001), Other in 1 of 6448 chromosomes (freq: 0.0002), Latino in 2 of 34396 chromosomes (freq: 0.00006), European in 13 of 125980 chromosomes (freq: 0.0001), Ashkenazi Jewish in 1 of 10126 chromosomes (freq: 0.0001), and South Asian in 6 of 30780 chromosomes (freq: 0.0002), while the variant was not observed in the East Asian, and European , populations. The p.Ile2541 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with multiple colorectal adenomas (Azzopardi et al., 2008); This variant is associated with the following publications: (PMID: 26373574, 21859464, 24728327, 24599579, 30836094, 34378333, 18199528) -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 05, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2021	The p.Ile2541Val variant in APC has been reported in 1 individual with multiple colorectal adenomas (Azzopardi 2008 PMID: 18199528), but has also been identified in a healthy adult (Bodian 2014 PMID: 24728327) and in 0.02% (6/30614) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). Isoleucine (Ile) at position 2541 is not well conserved: Four mammals (Chinese tree shrew, rabbit, pika, and star-nosed mole) carry a valine (Val) at this position despite high nearby amino acid conservation, suggesting that this change may be tolerated. Finally, this variant has been reported in ClinVar with conflicting interpretations (Likely Benign and Variant of Uncertain Significance; Variation ID# 133514). In summary, while the clinical significance of the p.Ile2541Val variant is uncertain, these data suggest that it is more likely to be benign. The ACMG/AMP Criteria applied: BP4. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 08, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 14, 2016	- -

not specified

Benign:2Other:1

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2024	Variant summary: APC c.7621A>G (p.Ile2541Val) results in a conservative amino acid change located in the basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 252814 control chromosomes (gnomAD). The observed variant frequency is approximately 1.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). c.7621A>G has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Azzopardi_2008), however no supportive evidence was provided for causality, in addition, the variant has also been reported in healthy controls (Bodian_2014). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 24728327, 18199528, 24599579, NO_PMID, 25882375). ClinVar contains an entry for this variant (Variation ID: 133514). Based on the evidence outlined above, the variant was classified as likely benign. -

Familial adenomatous polyposis 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.096

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.67

DEOGEN2

Benign

0.27

T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.82

.;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.067

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.28

N;N

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Benign

0.37

PROVEAN

Benign

0.34

N;N

REVEL

Uncertain

0.46

Sift

Benign

0.83

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.11

MVP

0.96

ClinPred

0.0044

GERP RS

0.87

Varity_R

0.028

gMVP

0.19

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