Submissions for variant NM_000038.6(APC):c.3386T>C (p.Leu1129Ser)

gnomAD frequency: 0.00250  dbSNP: rs143638171

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000077988	SCV000109820	benign	not specified	2013-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000034384	SCV000148992	benign	not provided	2018-07-03	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24599579, 22703879, 18199528, 22987206, 28608266, 25490678, 15122587, 22327622, 24728327, 21859464, 20223039, 20233475, 27153395, 28526081, 19029688, 22875147, 30361844)
Ambry Genetics	RCV000115083	SCV000185955	benign	Hereditary cancer-predisposing syndrome	2014-08-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV003534314	SCV000252583	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000077988	SCV000301592	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000393833	SCV000452005	likely benign	APC-Associated Polyposis Disorders	2018-06-12	criteria provided, single submitter	clinical testing	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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034384	SCV000602522	benign	not provided	2023-10-25	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000034384	SCV000610443	likely benign	not provided	2017-03-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115083	SCV000681596	benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034384	SCV000694031	likely benign	not provided	2016-09-02	criteria provided, single submitter	clinical testing	Variant summary: This c.3386T>C variant affects a conserved nucleotide, resulting in amino acid change from Leu to Ser. 2/3 in-silico tools used predict this variant to be damaging. This variant was found in 204/121934 control chromosomes including the broad and large populations from ExAC at a frequency of 0.001673, which is more than 27 times greater than the maximal expected frequency of a pathogenic allele (0.0000602) in this gene, suggesting this variant is benign. The variant particularly more common in European (Non-Finnish) population with allele frequency of 0.25% (171/66304 chromosomes) including two homozygotes. The variant has also been reported in cancer patients in literature, mainly of CRC and FAP patients, without strong evidence for causality. One reputable database (UMD) reports this variants co-occurrence in trans with complete APC gene deletion strongly suggesting for a benign outcome. In addition, the same database also reports finding of this variant in an unaffected relative, possibly suggesting a lack of cosegregation. In a small case-control study, this variant did not lead to an increased risk of CRC (Zhou_2004). Multiple clinical labs have classified this variant as benign/likely benign (4 labs) to uncertain significance (1 lab). Taken together, this variant has currently been classified as likely benign.
Mendelics	RCV000196915	SCV000838106	likely benign	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034384	SCV001154464	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	APC: BS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000034384	SCV002010887	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000077988	SCV002069699	benign	not specified	2021-06-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115083	SCV002535505	benign	Hereditary cancer-predisposing syndrome	2020-09-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000077988	SCV002550614	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115083	SCV004228132	benign	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034384	SCV000043121	no known pathogenicity	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Benign.
ITMI	RCV000077988	SCV000084182	not provided	not specified	2013-09-19	no assertion provided	reference population
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203169	SCV000257785	uncertain significance	Familial multiple polyposis syndrome	2015-04-14	flagged submission	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353808	SCV000591139	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Leu1129Ser variant was identified in 8 of 5346 proband chromosomes (frequency: 0.001) from individuals or families with familial adenomatous polyposis, and was present at a similar (slightly higher) frequency in control chromosomes from healthy individuals (frequency: 0.003), suggesting that this variant may not have clinical significance. (Azzopardi 2008, Bodian 2014, Friedl 2005, Johnston 2012, Lefevre 2012, Plawski 2008, Scott2004, Zhou 2004). In addition, the variant was identified in several cohorts from the general population at subpolymorphic allelic frequencies, increasing the likelihood that this may be a low frequency benign variant (populations include: Exome Aggregation Consortium (ExAC) database (frequency: 0.0026 in Non-Finnish individuals), 1000 Genomes Project (frequency: 0.001), Exome Variant server Exome Sequencing Project (frequency: 0.0024)). The variant was also identified in dbSNP (ID: rs143638171), UMD (6X as a neutral variant), HGMD, COSMIC, InSiGHT Colon Cancer Gene Variant Database, the ClinVar database (classified as benign by Emory Genetics Laboratory, Biesecker Laboratory, and Ambry Genetics; classified as likely benign by GeneDX), and in the GeneInsight COGR database (classified as likely/suspected benign by two clinical laboratories). In addition, a co-occurring pathogenic variant in the APC gene was identified in this patient, also increasing the likelihood that the p.Leu1129Ser variant is benign. Conservation and in silico programs contradict the above information and suggest a possible impact to the protein; however this computational information is not predictive enough to assume pathogenicity. (The residue is conserved across mammals but not in all organisms including african clawed frog; four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; one of five in silico splicing prediction programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts the creation of a potential 5’ splice site in the region of the variant, which is located outside of a known splicing consensus sequence). However, this variant was identified in one individual from our laboratory as co-occuring with a pathogenic APC variant, increasing the likelihood this variant is benign. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
True Health Diagnostics	RCV000115083	SCV000693477	likely benign	Hereditary cancer-predisposing syndrome	2017-10-16	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034384	SCV001742657	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034384	SCV001807973	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034384	SCV001917545	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000034384	SCV001927073	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034384	SCV001958243	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000034384	SCV002036537	likely benign	not provided		no assertion criteria provided	clinical testing