ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3386T>C (p.Leu1129Ser) (rs143638171)

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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance
Invitae RCV000196915 SCV000252583 benign Familial adenomatous polyposis 1 2020-12-07 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000203169 SCV000257785 uncertain significance Familial multiple polyposis syndrome 2015-04-14 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000077988 SCV000301592 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 RCV000077988 SCV000602522 benign not specified 2018-10-10 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 Health, Inc 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 Praxis fuer Humangenetik Tuebingen RCV000034384 SCV001154464 likely benign not provided 2021-03-01 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
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
Human Genetics - Radboudumc,Radboudumc RCV000034384 SCV001958243 likely benign not provided no assertion criteria provided clinical testing

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