5-112801324-C-T

Position:

chr5-112801324-C-T

Variant summary

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

The NM_000038.6(APC):c.775C>T(p.Arg259Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,612,680 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259Q) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:1

Conservation

PhyloP100: 2.67

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:

APC (HGNC:):

APC 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=0.26149353).

BS2

High AC in GnomAdExome4 at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APC	NM_000038.6 linkuse as main transcript	c.775C>T	p.Arg259Trp	missense_variant	8/16	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.775C>T	p.Arg259Trp	missense_variant	8/16	5	NM_000038.6	ENSP00000257430.4		P25054-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152042

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251012

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1460638

Hom.:

Cov.:

AF XY:

0.0000248

AC XY:

AN XY:

726624

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000706

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000494

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign: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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	the sequence change replaces arginine with tryptophan at codon 259 of the APC protein (p.Arg259Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs762117133, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411556). In-silico simulator software to predict the effect of missense changes on protein structure and function showed (SIFT: "Deleterious"; PolyPhen-2: "benign"). Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 259 of the APC protein (p.Arg259Trp). This variant is present in population databases (rs762117133, gnomAD 0.007%). This missense change has been observed in individual(s) with biliary tract cancer (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 411556). 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	Baylor Genetics	Nov 19, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 14, 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	Feb 13, 2018	- -

not provided

Uncertain:3

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, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.R259W variant was identified in the literature from one infant with Ewing-like sarcoma/undifferentiated round cell sarcoma who also had additional variants of uncertain significance in MSH6 (p.P1082S) and KMT2D (p.K2548E) (Xiong_2019_PMID:31702654). The variant was identified in dbSNP (ID: rs762117133), Cosmic and ClinVar (classified as uncertain significance by Counsyl, Invitae, Ambry Genetics, Color, True Health Diagnostics and Integrated Genetics). The variant was identified in control databases in 5 of 236492 chromosomes at a frequency of 0.00002114 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 2 of 30494 chromosomes (freq: 0.000066), East Asian in 1 of 17642 chromosomes (freq: 0.000057) and European (non-Finnish) in 2 of 102476 chromosomes (freq: 0.00002), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), or Other populations. The p.R259 residue is conserved in mammals and computational analyses (PolyPhen-2, MutationTaster, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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	Jul 03, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33309985, 31702654, 36243179, 32980694) -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 25, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 14, 2021	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	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 24, 2023	This missense variant replaces arginine with tryptophan at codon 259 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 an individual affected with sarcoma (PMID: 31702654). However, case-control studies reported no significant association with colorectal cancer or pancreatic cancer (PMID: 33309985, 32980694). This variant has been identified in 6/251012 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Nov 09, 2021

Variant summary: APC c.775C>T (p.Arg259Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251012 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.775C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis. These report(s) 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. 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

Jun 09, 2024

This missense variant replaces arginine with tryptophan at codon 259 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 an individual affected with sarcoma (PMID: 31702654). However, case-control studies reported no significant association with colorectal cancer or pancreatic cancer (PMID: 33309985, 32980694). This variant has been identified in 6/251012 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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 12, 2024

The APC c.775C>T variant is predicted to result in the amino acid substitution p.Arg259Trp. This variant has been reported in association with biliary tract cancer (Suppl Table 2, Okawa et al 2023. PubMed ID: 36243179). However, in a population-based screening for hereditary colorectal cancer, it was reported that this variant has no significant association with colorectal cancer (Fujita et al 2020. PubMed ID: 33309985). This variant is reported in 0.0065% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as a variant of uncertain significance by vast majority of the submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/411556/). 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

0.11

BayesDel_addAF

Uncertain

0.087

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.71

.;D;D;T

Eigen

Benign

0.10

Eigen_PC

Benign

0.079

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.97

D;.;D;D

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Uncertain

0.27

MutationAssessor

Uncertain

2.0

.;M;M;.

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.7

D;N;N;N

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.69, 0.66

MutPred

0.17

.;Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);

MVP

0.91

ClinPred

0.72

GERP RS

0.98

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.073

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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