rs201185479
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000038.6(APC):c.3625G>A(p.Glu1209Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,614,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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: 0.00011 ( 0 hom. )
Consequence
APC
NM_000038.6 missense
NM_000038.6 missense
Scores
6
13
Clinical Significance
Conservation
PhyloP100: 6.89
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.18611762).
BP6
Variant 5-112839219-G-A is Benign according to our data. Variant chr5-112839219-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 141688.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=6}.
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.3625G>A | p.Glu1209Lys | missense_variant | 16/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.3625G>A | p.Glu1209Lys | missense_variant | 16/16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+10247G>A | intron_variant | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.0000592 AC: 9AN: 152126Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
9
AN:
152126
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000399 AC: 10AN: 250566Hom.: 0 AF XY: 0.0000369 AC XY: 5AN XY: 135432
GnomAD3 exomes
AF:
AC:
10
AN:
250566
Hom.:
AF XY:
AC XY:
5
AN XY:
135432
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000111 AC: 162AN: 1461822Hom.: 0 Cov.: 33 AF XY: 0.000110 AC XY: 80AN XY: 727218
GnomAD4 exome
AF:
AC:
162
AN:
1461822
Hom.:
Cov.:
33
AF XY:
AC XY:
80
AN XY:
727218
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000591 AC: 9AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3AN XY: 74426
GnomAD4 genome
AF:
AC:
9
AN:
152244
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74426
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
4
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:7Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 17, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2017 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | APC: BP1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in at least one individual with a personal history of colon cancer who underwent multi-gene panel testing (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 29058119, 28135145) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 25, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 26, 2023 | This missense variant replaces glutamic acid with lysine at codon 1209 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 12/281956 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
APC-Associated Polyposis Disorders Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces glutamic acid with lysine at codon 1209 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 12/281956 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
APC-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 15, 2024 | The APC c.3625G>A variant is predicted to result in the amino acid substitution p.Glu1209Lys. This variant was reported in an individual with a history of colorectal cancer (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). This variant is reported in 0.0080% of alleles in individuals of African descent in gnomAD and has conflicting interpretations in ClinVar ranging from likely benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141688/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 16, 2023 | Variant summary: APC c.3625G>A (p.Glu1209Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 1614066 control chromosomes, predominantly at a frequency of 0.00013 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.8 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 Non-Finnish European origin. To our knowledge, no occurrence of c.3625G>A in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LB, n=3, VUS, n=6). Based on the evidence outlined above, the variant was classified as likely benign. - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
T;T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
D;D;D
Sift4G
Benign
T;T;T
Polyphen
B;B;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at