Submissions for variant NM_000038.6(APC):c.5465T>A (p.Val1822Asp)

gnomAD frequency: 0.82099  dbSNP: rs459552

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000020089	SCV003836607	benign	Familial adenomatous polyposis 1	2023-02-26	reviewed by expert panel	curation	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).
Eurofins Ntd Llc (ga)	RCV000035078	SCV000109828	benign	not specified	2016-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132160	SCV000187234	benign	Hereditary cancer-predisposing syndrome	2014-11-13	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV000035078	SCV000301601	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000358689	SCV000452027	benign	APC-Associated Polyposis Disorders	2018-03-06	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034393	SCV000602499	benign	not provided	2023-11-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000020089	SCV000647588	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132160	SCV000681741	benign	Hereditary cancer-predisposing syndrome	2015-03-27	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000020089	SCV000883261	benign	Familial adenomatous polyposis 1	2018-10-15	criteria provided, single submitter	curation	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.
GeneDx	RCV000034393	SCV001888577	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 27347161, 27153395, 9950360, 18343606, 20027139, 21859464, 24599579, 21995949, 20510605, 20149637, 16569251, 16574953, 22703879)
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000020089	SCV004017472	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996112	SCV004838056	benign	Classic or attenuated familial adenomatous polyposis	2024-02-05	criteria provided, single submitter	clinical testing
GeneReviews	RCV000020089	SCV000040395	not provided	Familial adenomatous polyposis 1		no assertion provided	literature only
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034393	SCV000043133	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035078	SCV000058718	benign	not specified	2008-03-01	no assertion criteria provided	clinical testing
ITMI	RCV000035078	SCV000084185	not provided	not specified	2013-09-19	no assertion provided	reference population
Systems Biology Platform Zhejiang California International NanoSystems Institute	RCV000074239	SCV000105832	cancer	Familial colorectal cancer		no assertion criteria provided	not provided	Converted during submission to other.
Pathway Genomics	RCV000020089	SCV000189854	benign	Familial adenomatous polyposis 1	2014-07-24	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035078	SCV000257016	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001270286	SCV000591191	benign	Familial multiple polyposis syndrome		no assertion criteria provided	clinical testing	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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000035078	SCV001740132	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035078	SCV001919186	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035078	SCV001953754	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000035078	SCV001972943	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000132160	SCV002050306	benign	Hereditary cancer-predisposing syndrome	2021-12-21	no assertion criteria provided	clinical testing