Submissions for variant NM_000038.6(APC):c.1635G>A (p.Ala545=)

gnomAD frequency: 0.59150  dbSNP: rs351771

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000411329	SCV003836588	benign	Familial adenomatous polyposis 1	2023-02-19	reviewed by expert panel	curation	The c.1635G>A (p.Ala545=) variant is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.82 (15756 in 19198 alleles) in the East Asian population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.001) 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, BP4, and BP7. (VCEP specifications version 1; date of approval: 12/12/2022).
Eurofins Ntd Llc (ga)	RCV000035066	SCV000109811	benign	not specified	2016-03-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000162371	SCV000212681	benign	Hereditary cancer-predisposing syndrome	2014-10-22	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	RCV000035066	SCV000301588	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000375983	SCV000451990	benign	APC-Associated Polyposis Disorders	2018-01-13	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.
Counsyl	RCV000411329	SCV000487816	benign	Familial adenomatous polyposis 1	2016-05-03	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001705642	SCV000602513	benign	not provided	2024-11-27	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411329	SCV000647190	benign	Familial adenomatous polyposis 1	2025-02-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162371	SCV000681480	benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001705642	SCV001915960	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000411329	SCV004017427	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035066	SCV000058706	benign	not specified	2008-03-01	no assertion criteria provided	clinical testing
Systems Biology Platform Zhejiang California International NanoSystems Institute	RCV000074153	SCV000105746	cancer	Familial colorectal cancer		no assertion criteria provided	not provided	Converted during submission to other.
Mayo Clinic Laboratories, Mayo Clinic	RCV000035066	SCV000256929	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353616	SCV000591083	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The c.1635G>A, p.Ala545Ala silent variant, located in exon 14 of APC, is not expected to have clinical significance because it does not alter an amino acid residue, is 9 bp away from the nearest splice junction, is listed in dbSNP (rs_id: rs351771) with a heterozygosity frequency of 0.479+/-0.099. Based on the above information, this is a likely benign variant.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000035066	SCV001740937	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035066	SCV001920318	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035066	SCV001951258	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000035066	SCV001968895	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162371	SCV002050300	benign	Hereditary cancer-predisposing syndrome	2021-12-21	no assertion criteria provided	clinical testing