rs587782886
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP3BP6BS2
The NM_000038.6(APC):c.1139G>A(p.Arg380Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000096 ( 0 hom. )
Consequence
APC
NM_000038.6 missense
NM_000038.6 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 10.0
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 Likely_benign. Variant got -4 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.781
BP6
Variant 5-112819171-G-A is Benign according to our data. Variant chr5-112819171-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 143004.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=1, Uncertain_significance=1}.
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.1139G>A | p.Arg380Gln | missense_variant | 10/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1139G>A | p.Arg380Gln | missense_variant | 10/16 | 5 | NM_000038.6 | ENSP00000257430 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152138Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000838 AC: 21AN: 250708Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135482
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GnomAD4 exome AF: 0.0000965 AC: 141AN: 1461688Hom.: 0 Cov.: 33 AF XY: 0.0000908 AC XY: 66AN XY: 727136
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GnomAD4 genome AF: 0.0000592 AC: 9AN: 152138Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74318
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:10
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:1Benign:2
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 21, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 29, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 28, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 27, 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 03, 2022 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 30, 2022 | Variant summary: APC c.1139G>A (p.Arg380Gln) results in a conservative amino acid change located in the Armadillo repeat of 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 8.4e-05 in 250708 control chromosomes, predominantly at a frequency of 0.00029 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 4.0 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1139G>A has been reported in the literature in settings of multigene panel testing among individuals affected with Familial Adenomatous Polyposis/colorectal cancer (example, Kerr_2013, Hansen_2017, Castellanos_2017). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign (n=5) (VUS, n=2). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 21, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2021 | This variant is associated with the following publications: (PMID: 28195393, 23159591, 28051113) - |
APC-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 26, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;D;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
.;M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Uncertain
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
1.0
.;D;D;.
Vest4
0.90, 0.73
MutPred
0.34
.;Gain of ubiquitination at K377 (P = 0.0328);Gain of ubiquitination at K377 (P = 0.0328);Gain of ubiquitination at K377 (P = 0.0328);
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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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