rs459552
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BA1BP1
This summary comes from the ClinGen Evidence Repository: The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC VCEP threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA010422/MONDO:0021056/089
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.5465T>A | p.Val1822Asp | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.5465T>A | p.Val1822Asp | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.820 AC: 124670AN: 152042Hom.: 51821 Cov.: 31
GnomAD3 exomes AF: 0.795 AC: 199083AN: 250474Hom.: 79771 AF XY: 0.789 AC XY: 106909AN XY: 135464
GnomAD4 exome AF: 0.777 AC: 1133202AN: 1459012Hom.: 441782 Cov.: 53 AF XY: 0.776 AC XY: 563110AN XY: 725998
GnomAD4 genome ? AF: 0.820 AC: 124789AN: 152160Hom.: 51880 Cov.: 31 AF XY: 0.816 AC XY: 60692AN XY: 74374
ClinVar
Submissions by phenotype
not specified Benign:8Other:1
Benign, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 16, 2016 | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 01, 2008 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Familial adenomatous polyposis 1 Benign:5Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | Oct 15, 2018 | This variant is interpreted as Benign for Familial adenomatous polyposis 1. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
Benign, reviewed by expert panel | curation | ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel | Feb 26, 2023 | The c.5465T>A variant in APC is a missense variant predicted to cause the substitution of Valine by Asparagine at amino acid position 1822 (p.Val1822Asp). APC is defined by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) as a gene for which primarily truncating variants are known to cause disease (BP1). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9598 (23897/24898 alleles) in the African/African American population, which is higher than the ClinGen APC VCEP threshold (>0.1%) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1 and BP1 (VCEP specifications version 1; date of approval: 12/12/2022). - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 30, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | This variant is associated with the following publications: (PMID: 24728327, 27347161, 27153395, 9950360, 18343606, 20027139, 21859464, 24599579, 21995949, 20510605, 20149637, 16569251, 16574953, 22703879) - |
Benign, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Benign, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Dec 21, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 13, 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 27, 2015 | - - |
Familial multiple polyposis syndrome Benign:1
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | This p.Val1822Asp variant is not expected to have clinical significance because this residue is not conserved and the variant amino acid (Asp) is present in other mammals such as chimp, macaque, rat and dog as well as some lower evolutionary species, increasing the likelihood that this is a benign variant. In addition, it is not located near a splice junction, and is listed in dbSNP (id:rs459552) with a minor allele frequency of 0.140 in a Caucasian population. The clinical relevance of this variant is still under debate, since some studies showed that it could act as a low-penetrance allele that increases the risk of developing colorectal cancer (CRC) while others consider it as a common polymorphism without clinical consequences (Picelli_2010_20149637). In summary, based on the above information, the p.Val1822Asp variant is predicted to be benign, but we cannot rule out the possibility that this may be a low-penetrance polymorphic allele that increases risk of CRC. - |
APC-Associated Polyposis Disorders Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
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 | - - |
Familial colorectal cancer Other:1
other, no assertion criteria provided | literature only | Systems Biology Platform Zhejiang California International NanoSystems Institute | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at