Submissions for variant NM_000038.6(APC):c.705A>G (p.Leu235=)

gnomAD frequency: 0.00213  dbSNP: rs147036141

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV002514368	SCV003836570	benign	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.705A>G (p.Leu235=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing by multiple splicing predictors including SpliceAI, VarSEAK and MaxEntScan (BP4, BP7). This variant has been observed 3 times in homozygous state in gnomAD 2.1.1 (BS2). The highest population minor allele frequency in the non-cancer population of gnomAD v2.1.1 is 0.004669 in the Finnish 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, BS2, BP4, and BP7 (Specification Version 1.0; date of approval: 12/12/2022).
Eurofins Ntd Llc (ga)	RCV000077993	SCV000109830	benign	not specified	2012-09-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000077993	SCV000167020	benign	not specified	2014-01-27	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000123677	SCV000212748	likely benign	Hereditary cancer-predisposing syndrome	2014-07-24	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV003315600	SCV000252593	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000276575	SCV000451985	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679083	SCV000602537	benign	not provided	2023-10-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000123677	SCV000681844	benign	Hereditary cancer-predisposing syndrome	2016-03-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679083	SCV000805461	likely benign	not provided	2017-02-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000077993	SCV002069696	likely benign	not specified	2022-01-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123677	SCV002527379	benign	Hereditary cancer-predisposing syndrome	2020-08-31	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000077993	SCV002550570	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679083	SCV002586065	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	APC: BP4, BP7, BS1, BS2
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000123677	SCV002819250	benign	Hereditary cancer-predisposing syndrome	2022-12-20	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315600	SCV004015859	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000077993	SCV000257028	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353583	SCV000591049	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Leu235Leu variant is not expected to have clinical significance because it does not alter an amino acid residue and is not located near a splice junction. It has been reported in the UMD (x1) and LOVD (x2) databases. In addition, it is observed as a low frequency variant in the ESP cohort, increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, this variant is predicted benign.
True Health Diagnostics	RCV000123677	SCV000693488	likely benign	Hereditary cancer-predisposing syndrome	2017-10-10	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000077993	SCV001743904	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000679083	SCV001798801	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000679083	SCV001808210	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000077993	SCV001921686	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679083	SCV001951960	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000679083	SCV001964968	likely benign	not provided		no assertion criteria provided	clinical testing