5-112838980-T-C
Variant names:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000038.6(APC):โc.3386T>Cโ(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 (โ โ ).
Frequency
Genomes: ๐ 0.0024 ( 0 hom., cov: 32)
Exomes ๐: 0.0043 ( 23 hom. )
Consequence
APC
NM_000038.6 missense
NM_000038.6 missense
Scores
1
10
8
Clinical Significance
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]
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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
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 0.00241 AC: 367AN: 152158Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00187 AC: 470AN: 250734Hom.: 2 AF XY: 0.00185 AC XY: 251AN XY: 135548
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GnomAD4 exome AF: 0.00434 AC: 6343AN: 1461832Hom.: 23 Cov.: 33 AF XY: 0.00435 AC XY: 3166AN XY: 727218
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GnomAD4 genome 0.00241 AC: 367AN: 152276Hom.: 0 Cov.: 32 AF XY: 0.00224 AC XY: 167AN XY: 74456
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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 | 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, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
| 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 | 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 | 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, 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 | - | - - |
| 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, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2025 | APC: BS2 - |
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. - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 21, 2016 | - - |
| 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 | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Sep 21, 2023 | - - |
not specified Benign:4Other:1
| 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 | Mar 04, 2025 | - - |
| 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 | - - |
Familial adenomatous polyposis 1 Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2025 | - - |
| 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 | - - |
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 5รขโฌลกรโรยด 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
.;L;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Benign
T;T;T;T
Polyphen
0.42
.;B;B;.
Vest4
0.78, 0.81
MVP
ClinPred
T
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at