chr5-112838032-A-G

Position:

chr5-112838032-A-G

Variant summary

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

The NM_000038.6(APC):c.2438A>G(p.Asn813Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,614,048 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N813H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:5

Conservation

PhyloP100: 1.61

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=0.030400693).

BP6

Variant 5-112838032-A-G is Benign according to our data. Variant chr5-112838032-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41499.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=5}.

BS2

High AC in GnomAd4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6 linkuse as main transcript	c.2438A>G	p.Asn813Ser	missense_variant	16/16	ENST00000257430.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
APC	ENST00000257430.9 linkuse as main transcript	c.2438A>G	p.Asn813Ser	missense_variant	16/16	5	NM_000038.6	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000518

AC:

AN:

250876

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135644

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000617

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000267

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.000232

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000980

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000576

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2019	This variant is denoted APC c.2438A>G at the cDNA level, p.Asn813Ser (N813S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in an individual with colorectal cancer and in another with a personal and family history of pancreatic cancer (Yurgelun 2017, Chaffee 2018). Additionally, APC Asn813Ser was studied in a melanoma cell line, which displayed no increase of Axin2 expression and no increase of Wnt signaling (Worm 2004). APC Asn813Ser was observed at an allele frequency of 0.02% (5/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Asn813Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2022	The APC c.2438A>G; p.Asn813Ser variant (rs201522866) is reported in the literature in individuals with colorectal or pancreatic cancer (Chaffee 2018, Erdem 2020, Yurgelun 2017), and is reported in ClinVar (Variation ID: 41499). This variant is found in the general population with an overall allele frequency of 0.005% (15/282270 alleles) in the Genome Aggregation Database. The asparagine at codon 813 is moderately conserved, but computational analyses predict that this variant is tolerated (REVEL: 0.13). The vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). However, based on available information, the clinical significance of this variant is uncertain at this time. References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. Chaffee KG et al. Prevalence of germ-line mutations in cancer genes among pancreatic cancer patients with a positive family history. Genet Med. 2018 Jan;20(1):119-127. PMID: 28726808. Erdem HB et al. Spectrum of germline cancer susceptibility gene mutations in Turkish colorectal cancer patients: a single center study. Turk J Med Sci. 2020 Jun 23;50(4):1015-1021. PMID: 32283892. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. PMID: 28135145 -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 31, 2017	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 27, 2019	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. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Sep 08, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 10, 2016	- -

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 19, 2020	Variant summary: APC c.2438A>G (p.Asn813Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 252020 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (5.6e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.2438A>G has been reported in the literature in individuals affected with colorectal cancer or pancreatic cancer (Yurgelun_2017, Erdem_2020, Chaffee_2018). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. A functional study indicates the variant does not affect downstream targets in the WNT pathway and therefore suggest this variant does not affect APC protein function (Worm_2004). However, the functional significance of these findings are not clear. Six other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=4) or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Familial adenomatous polyposis 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.2

DANN

Benign

0.70

DEOGEN2

Uncertain

0.51

.;D;D;T

Eigen

Benign

-0.68

Eigen_PC

Benign

-0.51

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.88

D;.;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.030

T;T;T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

-0.18

.;N;N;.

MutationTaster

Benign

0.71

N;N;N

PrimateAI

Benign

0.34

PROVEAN

Benign

0.40

N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.42

T;T;T;T

Sift4G

Benign

0.92

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.10, 0.069

MVP

0.66

ClinPred

0.019

GERP RS

-1.8

Varity_R

0.020

gMVP

0.15

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