5-112838980-T-C

Variant names:

• chr5-112838980-T-C
• rs143638171
• NM_000038.6:c.3386T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0043 (23 hom.)
• Consequence: APC NM_000038.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:27 O:1
• Conservation: PhyloP100: 4.60

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]

ENSG00000258864 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
APC	NM_000038.6	c.3386T>C	p.Leu1129Ser	missense_variant	Exon 16 of 16	ENST00000257430.9	NP_000029.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APC	ENST00000257430.9	c.3386T>C	p.Leu1129Ser	missense_variant	Exon 16 of 16	5	NM_000038.6	ENSP00000257430.4
ENSG00000258864	ENST00000520401.1	n.228+10008T>C		intron_variant	Intron 3 of 7	3		ENSP00000454861.1

Frequencies

GnomAD3 genomes AF: 0.00241 AC: 367 AN: 152158 Hom.: 0 Cov.: 32

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.: 2 AF XY: 0.00185 AC XY: 251 AN XY: 135548

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.: 23 Cov.: 33 AF XY: 0.00435 AC XY: 3166 AN XY: 727218

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.: 0 Cov.: 32 AF XY: 0.00224 AC XY: 167 AN XY: 74456

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.: 2

Bravo AF: 0.00244

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00161 AC: 195

EpiCase AF: 0.00447

EpiControl AF: 0.00344

ClinVar

Significance: Benign/Likely benign

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:13

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 25, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
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) -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 20, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	APC: BS2 -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 16, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 17, 2020	- -
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	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. -

not specified Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2013	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 17, 2021	- -

Familial adenomatous polyposis 1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2025	- -

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

- -

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 5’ 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. -

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. -

Classic or attenuated familial adenomatous polyposis Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	23
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	D
LIST_S2	Uncertain	0.88	D;.;D;D
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.0097	T;T;T;T
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.90	.;L;L;.
PrimateAI	Uncertain	0.61	T
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	T
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

Other links and lift over

dbSNP: rs143638171; hg19: chr5-112174677; COSMIC: COSV57322709; COSMIC: COSV57322709;