5-112838464-A-G

Position:

chr5-112838464-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000038.6(APC):c.2870A>G(p.Lys957Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000681 in 1,614,132 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.77

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.23263535).

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.2870A>G	p.Lys957Arg	missense_variant	16/16	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.2870A>G	p.Lys957Arg	missense_variant	16/16	5	NM_000038.6	ENSP00000257430.4		P25054-1
ENSG00000258864	ENST00000520401.1 linkuse as main transcript	n.228+9492A>G		intron_variant		3		ENSP00000454861.1		H3BNH8

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250958

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135616

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152280

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.000131

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:

0.0000282

Hom.:

Bravo

AF:

0.000106

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial adenomatous polyposis 1

Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 957 of the APC protein (p.Lys957Arg). This variant is present in population databases (rs777881096, gnomAD 0.006%). 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: 231960). 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	Myriad Genetics, Inc.	Feb 15, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 16, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 19, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Jan 14, 2024	The APC c.2870A>G (p.Lys957Arg) missense change has a maximum subpopulation frequency of 0.002% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, but functional studies have not been performed. This variant has not been reported in the literature in individuals with APC-related disease. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.? -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 03, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2024	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic and other cancers (PMID: 29684080, 34034685, 35534704, 35980532); This variant is associated with the following publications: (PMID: 34034685, 35534704, 29684080, 35980532, 37306523) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 13, 2024	The APC c.2870A>G (p.Lys957Arg) variant has been reported in the published literature in individuals with a personal or family history of breast cancer (PMIDs: 35980532 (2022), 35534704 (2022)), pancreatic cancer, thyroid cancer, and kidney cancer (PMIDs: 34034685 (2021), 29684080 (2018)). This variant has also been observed in a reportedly healthy individual who had a family history of hereditary cancer (PMID: 37306523 (2023)). The frequency of this variant in the general population, 0.000008 (2/250958 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. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 16, 2023	This missense variant replaces lysine with arginine at codon 957 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 been reported in individuals affected with breast, thyroid, and kidney cancer (PMID: 29684080, 34034685) as well as in unaffected individuals (PMID: 30267214, 34034685). This variant has been identified in 2/250958 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 24, 2024	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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jul 08, 2024

Variant summary: APC c.2870A>G (p.Lys957Arg) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250958 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2870A>G has been reported in the literature in individuals with high risk, breast and/or thyroid cancer, and those undergoing breast and ovary screening as well as in an unaffected individual (example: AlHarbi_2023, de Oliveira_2022, Pereira_2022, Rapposelli _2021). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrence with another pathogenic variant has been reported (MSH6 c.1883G>A, p.Trp628*; AlHarbi _2023) for this variant. 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: 37306523, 32999869, 35980532, 34034685, 35534704). ClinVar contains an entry for this variant (Variation ID: 231960). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Classic or attenuated familial adenomatous polyposis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Aug 06, 2024

This missense variant replaces lysine with arginine at codon 957 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 been reported in individuals affected with breast, thyroid, and kidney cancer (PMID: 29684080, 34034685), as well as in unaffected individuals (PMID: 30267214, 34034685). This variant has been identified in 2/250958 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.0048

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.55

.;D;D;T

Eigen

Benign

0.028

Eigen_PC

Benign

0.21

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D;D

M_CAP

Benign

0.049

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Uncertain

2.1

.;M;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.43

N;N;N;N

REVEL

Uncertain

0.29

Sift

Benign

0.30

T;T;T;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.36

.;B;B;.

Vest4

0.35, 0.37

MutPred

0.24

.;Loss of ubiquitination at K957 (P = 6e-04);Loss of ubiquitination at K957 (P = 6e-04);Loss of ubiquitination at K957 (P = 6e-04);

MVP

0.83

ClinPred

0.096

GERP RS

5.8

Varity_R

0.093

gMVP

0.16

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