rs374380039

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_000038.6(APC):​c.3242G>A​(p.Ser1081Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,028 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 1.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06665996).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
APCNM_000038.6 linkc.3242G>A p.Ser1081Asn missense_variant Exon 16 of 16 ENST00000257430.9 NP_000029.2 P25054-1Q4LE70

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
APCENST00000257430.9 linkc.3242G>A p.Ser1081Asn missense_variant Exon 16 of 16 5 NM_000038.6 ENSP00000257430.4 P25054-1
ENSG00000258864ENST00000520401.1 linkn.228+9864G>A intron_variant Intron 3 of 7 3 ENSP00000454861.1 H3BNH8

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461826
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152202
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000483
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000329
Hom.:
0
Bravo
AF:
0.0000302
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1 Uncertain:4
Feb 24, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 15, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

May 03, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 16, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1081 of the APC protein (p.Ser1081Asn). This variant is present in population databases (rs374380039, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 219459). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Jul 12, 2021
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Apr 26, 2023
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 1081 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Jun 15, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Uncertain:2
Feb 20, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The APC c.3242G>A (p.Ser1081Asn) variant has been reported in the published literature in an individual with melanoma (PMID: 32913981 (2018)). It has also been reported in a renal cell carcinoma sample from The Cancer Genome Atlas (TCGA) dataset (PMID: 29684080 (2018)). The frequency of this variant in the general population, 0.000032 (1/31396 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Feb 23, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in an individual with kidney cancer (PMID: 29684080); This variant is associated with the following publications: (PMID: 18199528, 29684080) -

Classic or attenuated familial adenomatous polyposis Uncertain:1
May 16, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This missense variant replaces serine with asparagine at codon 1081 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/31396 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

APC-related disorder Uncertain:1
May 05, 2024
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The APC c.3242G>A variant is predicted to result in the amino acid substitution p.Ser1081Asn. This variant has been reported with another missense variant in the gene APC in an individual from a cohort study on patients with features of Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (S9_Table. Yehia et al 2018. PubMed ID: 29684080). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance by majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/219459/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Benign
-0.088
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
6.8
DANN
Benign
0.51
DEOGEN2
Benign
0.36
.;T;T;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.85
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Benign
0.77
T;.;T;T
M_CAP
Benign
0.057
D
MetaRNN
Benign
0.067
T;T;T;T
MetaSVM
Benign
-0.62
T
MutationAssessor
Benign
0.46
.;N;N;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.010
N;N;N;N
REVEL
Benign
0.24
Sift
Benign
0.60
T;T;T;T
Sift4G
Benign
0.33
T;T;T;T
Polyphen
0.0
.;B;B;.
Vest4
0.068, 0.084
MVP
0.62
ClinPred
0.032
T
GERP RS
0.51
Varity_R
0.024
gMVP
0.25

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.

Other links and lift over

dbSNP: rs374380039; hg19: chr5-112174533; API