5-112839105-C-T

Position:

chr5-112839105-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000038.6(APC):c.3511C>T(p.Arg1171Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,613,954 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1171H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00028 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 3 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:17O:1

Conservation

PhyloP100: 3.72

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.041510195).

BP6

Variant 5-112839105-C-T is Benign according to our data. Variant chr5-112839105-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 133518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112839105-C-T is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6 linkuse as main transcript	c.3511C>T	p.Arg1171Cys	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.3511C>T	p.Arg1171Cys	missense_variant	16/16	5	NM_000038.6	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

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:

0.000235

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.000344

AC:

AN:

250294

Hom.:

AF XY:

0.000302

AC XY:

AN XY:

135550

show subpopulations

Gnomad AFR exome

AF:

0.0000633

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000309

Gnomad OTH exome

AF:

0.00115

GnomAD4 exome

AF:

0.000375

AC:

548

AN:

1461716

Hom.:

Cov.:

AF XY:

0.000353

AC XY:

257

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.00125

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:

0.000391

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000276

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00111

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000436

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	APC: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2021	This variant is associated with the following publications: (PMID: 23292937, 26976419, 24599579, 24728327, 25980754, 19642502, 9950360, 25981591, 24163242) -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2016	Variant summary: The APC c.3511C>T (p.Arg1171Cys) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 38/120476 control chromosomes (1 homozygote), predominantly observed in the Latino subpopulation at a frequency of 0.0014724 (17/11546). This frequency is about 21 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. This variant has been reported in an affected individual with no evidence for causality, and authors classified this variant as polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as likely benign. -

Familial adenomatous polyposis 1

Benign:4

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 21, 2024	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 19, 2018	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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 09, 2020	- -

not specified

Benign:2Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Carcinoma of colon

Uncertain:1Benign:1

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The APC p.Arg1171Cys variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0002) from individuals or families with lynch syndrome and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs201830995) as "With Likely benign allele ", ClinVar (classified as benign by Invitae and one clinical laboratory; as likely benign by Ambry Genetics, GeneDx and three clinical laboratories), Cosmic (6x in Stomach, Large intestine, Haematopoietic and lymphoid tissue or Endometrium), MutDB, LOVD 3.0 (4x), and in UMD-LSDB (1x likely neutral), databases. The variant was not identified in COGR, or Zhejiang University, databases. The variant was identified in control databases in 98 of 276674 chromosomes (2 homozygous) at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24006 chromosomes (freq: 0.0002), Other in 11 of 6450 chromosomes (freq: 0.002), Latino in 44 of 34406 chromosomes (freq: 0.001), European in 38 of 126368 chromosomes (freq: 0.0003), and South Asian in 1 of 30774 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Arg1171 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) 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 this variant meets our laboratory's criteria to be classified as benign. -
Uncertain significance, no assertion criteria provided	clinical testing	3DMed Clinical Laboratory Inc	Jul 24, 2017	- -

Familial multiple polyposis syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Jul 30, 2015

- -

Gastric cancer;C0346629:Colorectal cancer;C1851124:Desmoid disease, hereditary;C2239176:Hepatocellular carcinoma;C2713442:Familial adenomatous polyposis 1;C4749917:Gastric adenocarcinoma and proximal polyposis of the stomach

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 25, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

D;D;T

Eigen

Benign

-0.12

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.93

.;D;D

M_CAP

Benign

0.038

MetaRNN

Benign

0.042

T;T;T

MetaSVM

Benign

-0.59

MutationAssessor

Benign

0.0

N;N;.

MutationTaster

Benign

0.92

N;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-1.5

N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.011

D;D;D

Sift4G

Uncertain

0.048

D;D;T

Polyphen

0.092

B;B;.

Vest4

0.29

MVP

0.84

ClinPred

0.025

GERP RS

5.6

Varity_R

0.16

gMVP

0.57

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