5-112838980-T-C

Position:

chr5-112838980-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000038.6(APC):c.3386T>C(p.Leu1129Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00416 in 1,614,108 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts 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. L1129F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0043 ( 23 hom. )

Consequence

APC
NM_000038.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:27O:1

Conservation

PhyloP100: 4.60

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009671479).

BP6

Variant 5-112838980-T-C is Benign according to our data. Variant chr5-112838980-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 41502.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-112838980-T-C is described in Lovd as [Likely_benign]. Variant chr5-112838980-T-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00241 (367/152276) while in subpopulation NFE AF= 0.00376 (256/68034). AF 95% confidence interval is 0.00338. There are 0 homozygotes in gnomad4. There are 167 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 367 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
APC	NM_000038.6 linkuse as main transcript	c.3386T>C	p.Leu1129Ser	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.3386T>C	p.Leu1129Ser	missense_variant	16/16	5	NM_000038.6	P1	P25054-1

Frequencies

GnomAD3 genomes

AF:

0.00241

AC:

367

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000821

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.00347

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00376

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00187

AC:

470

AN:

250734

Hom.:

AF XY:

0.00185

AC XY:

251

AN XY:

135548

show subpopulations

Gnomad AFR exome

AF:

0.000803

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.00349

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00434

AC:

6343

AN:

1461832

Hom.:

Cov.:

AF XY:

0.00435

AC XY:

3166

AN XY:

727218

show subpopulations

Gnomad4 AFR exome

AF:

0.000956

Gnomad4 AMR exome

AF:

0.00150

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.000449

Gnomad4 NFE exome

AF:

0.00538

Gnomad4 OTH exome

AF:

0.00379

GnomAD4 genome

AF:

0.00241

AC:

367

AN:

152276

Hom.:

Cov.:

AF XY:

0.00224

AC XY:

167

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000818

Gnomad4 AMR

AF:

0.00346

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.00376

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00324

Hom.:

Bravo

AF:

0.00244

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00161

AC:

195

EpiCase

AF:

0.00447

EpiControl

AF:

0.00344

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:27Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:13

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	APC: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 02, 2016	Variant summary: This c.3386T>C variant affects a conserved nucleotide, resulting in amino acid change from Leu to Ser. 2/3 in-silico tools used predict this variant to be damaging. This variant was found in 204/121934 control chromosomes including the broad and large populations from ExAC at a frequency of 0.001673, which is more than 27 times greater than the maximal expected frequency of a pathogenic allele (0.0000602) in this gene, suggesting this variant is benign. The variant particularly more common in European (Non-Finnish) population with allele frequency of 0.25% (171/66304 chromosomes) including two homozygotes. The variant has also been reported in cancer patients in literature, mainly of CRC and FAP patients, without strong evidence for causality. One reputable database (UMD) reports this variants co-occurrence in trans with complete APC gene deletion strongly suggesting for a benign outcome. In addition, the same database also reports finding of this variant in an unaffected relative, possibly suggesting a lack of cosegregation. In a small case-control study, this variant did not lead to an increased risk of CRC (Zhou_2004). Multiple clinical labs have classified this variant as benign/likely benign (4 labs) to uncertain significance (1 lab). Taken together, this variant has currently been classified as likely benign. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2018	This variant is associated with the following publications: (PMID: 24599579, 22703879, 18199528, 22987206, 28608266, 25490678, 15122587, 22327622, 24728327, 21859464, 20223039, 20233475, 27153395, 28526081, 19029688, 22875147, 30361844) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Hereditary cancer-predisposing syndrome

Benign:5

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 11, 2014	This alteration is classified as 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, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 16, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 21, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 21, 2023	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 17, 2020	- -

not specified

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 17, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Familial adenomatous polyposis 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -

Familial multiple polyposis syndrome

Uncertain:1

Uncertain significance, flagged submission

clinical testing

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

Apr 14, 2015

- -

APC-Associated Polyposis Disorders

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 12, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Carcinoma of colon

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The APC p.Leu1129Ser variant was identified in 8 of 5346 proband chromosomes (frequency: 0.001) from individuals or families with familial adenomatous polyposis, and was present at a similar (slightly higher) frequency in control chromosomes from healthy individuals (frequency: 0.003), suggesting that this variant may not have clinical significance. (Azzopardi 2008, Bodian 2014, Friedl 2005, Johnston 2012, Lefevre 2012, Plawski 2008, Scott2004, Zhou 2004). In addition, the variant was identified in several cohorts from the general population at subpolymorphic allelic frequencies, increasing the likelihood that this may be a low frequency benign variant (populations include: Exome Aggregation Consortium (ExAC) database (frequency: 0.0026 in Non-Finnish individuals), 1000 Genomes Project (frequency: 0.001), Exome Variant server Exome Sequencing Project (frequency: 0.0024)). The variant was also identified in dbSNP (ID: rs143638171), UMD (6X as a neutral variant), HGMD, COSMIC, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as benign by Emory Genetics Laboratory, Biesecker Laboratory, and Ambry Genetics; classified as likely benign by GeneDX), and in the GeneInsight COGR database (classified as likely/suspected benign by two clinical laboratories). In addition, a co-occurring pathogenic variant in the APC gene was identified in this patient, also increasing the likelihood that the p.Leu1129Ser variant is benign. Conservation and in silico programs contradict the above information and suggest a possible impact to the protein; however this computational information is not predictive enough to assume pathogenicity. (The residue is conserved across mammals but not in all organisms including african clawed frog; four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; one of five in silico splicing prediction programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a potential 5â€šÃ„Ã´ splice site in the region of the variant, which is located outside of a known splicing consensus sequence). However, this variant was identified in one individual from our laboratory as co-occuring with a pathogenic APC variant, increasing the likelihood this variant is benign. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Classic or attenuated familial adenomatous polyposis

Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Feb 05, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.049

BayesDel_noAF

Pathogenic

0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.40

.;T;T;T

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

D;.;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.0097

T;T;T;T

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.90

.;L;L;.

MutationTaster

Benign

0.82

D;D;D

PrimateAI

Uncertain

0.61

PROVEAN

Benign

0.52

N;N;N;N

REVEL

Uncertain

0.42

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Benign

0.43

T;T;T;T

Polyphen

0.42

.;B;B;.

Vest4

0.78, 0.81

MVP

0.99

ClinPred

0.040

GERP RS

5.8

Varity_R

0.090

gMVP

0.40

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