rs539108537

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000038.6(APC):c.95A>G(p.Asn32Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000409 in 1,613,816 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 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:5

Conservation

PhyloP100: 5.70

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10540694).

BP6

Variant 5-112754985-A-G is Benign according to our data. Variant chr5-112754985-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 218010.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6}.

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.95A>G	p.Asn32Ser	missense_variant	2/16	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.95A>G	p.Asn32Ser	missense_variant	2/16	5	NM_000038.6	ENSP00000257430	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

251256

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135776

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000363

AC:

AN:

1461510

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727058

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000115

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2024	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with colorectal or breast cancer, and also in controls in a case-control study of biliary tract cancer (PMID: 18199528, 26976419, 29237405, 32658311, 36243179); This variant is associated with the following publications: (PMID: 29237405, 26976419, 26900293, 27908614, 32658311, 18199528, 36243179) -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 05, 2018	- -

not specified

Uncertain:1Benign:2

Uncertain significance, no assertion criteria provided	research	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 03, 2024	Variant summary: APC c.95A>G (p.Asn32Ser) results in a conservative amino acid change located in the adenomatous polyposis coli, N-terminal dimerisation domain (IPR032038) 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 7.9e-05 in 252236 control chromosomes (gnomAD, Akcay_2020). The variant allele was found at a frequency of 4.3e-05 in 1614796 control chromosomes, predominantly at a frequency of 0.00019 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). The variant has been found as a germline and somatic variant in patients with various cancers including but not limited to colorectal cancer, non-small cell lung cancer, and breast cancer without strong evidence for or against pathogenicity (example: Chang_2016, Lv_2017, Tung_2016, Lee_2017, Akcay_2020, Pavan_2021) as well as in controls (Akcay_2020, Okawa_2022). 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: 26900293, 26976419, 28380452, 32658311, 29237405, 36243179, 33569305). ClinVar contains an entry for this variant (Variation ID: 218010). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Dec 28, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 07, 2022	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 16, 2016	- -

Familial adenomatous polyposis 1

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 32 of the APC protein (p.Asn32Ser). This variant is present in population databases (rs539108537, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and colon cancer (PMID: 26976419, 29237405). ClinVar contains an entry for this variant (Variation ID: 218010). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Neoplasm of stomach

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

3DMed Clinical Laboratory Inc

Jan 25, 2018

- -

Classic or attenuated familial adenomatous polyposis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.24

T;T;T;T

Eigen

Benign

-0.17

Eigen_PC

Benign

0.035

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

T;.;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.11

T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.94

.;L;L;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.12

N;N;N;N

REVEL

Uncertain

0.32

Sift

Benign

0.95

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.49

.;P;P;.

Vest4

0.36, 0.34

MVP

0.77

ClinPred

0.093

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.11

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