ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5801C>T (p.Pro1934Leu)

gnomAD frequency: 0.00012  dbSNP: rs587780600
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002228632 SCV000166044 likely benign Familial adenomatous polyposis 1 2021-12-12 criteria provided, single submitter clinical testing
GeneDx RCV000656747 SCV000209534 likely benign not provided 2020-03-16 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 18199528, 27150160, 26580448, 21901162, 25925381, 21859464, 26845104, 28873162, 29684080, 29641532)
Ambry Genetics RCV000159562 SCV000213581 benign Hereditary cancer-predisposing syndrome 2020-06-12 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
CSER _CC_NCGL, University of Washington RCV000210900 SCV000264591 uncertain significance Familial multiple polyposis syndrome 2015-12-01 criteria provided, single submitter research
University of Washington Department of Laboratory Medicine,University of Washington RCV000210078 SCV000266143 uncertain significance Colorectal cancer, susceptibility to 2015-11-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000211923 SCV000538300 uncertain significance not specified 2016-03-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 report in probands; ExAC: 6/11510 Latino; ClinVar: 3 VUS
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656747 SCV000600120 likely benign not provided 2020-09-10 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000159562 SCV000681763 uncertain significance Hereditary cancer-predisposing syndrome 2021-07-30 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 1934 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal polyps (PMID: 18199528), pancreatic cancer (PMID: 32980694), breast cancer (PMID: 26845104), uterine cancer (PMID: 29684080), and unspecified cancer (PMID: 28873162). This variant has been identified in 38/281366 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in multiple healthy control individuals (PMID: 32980694). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics RCV000122787 SCV000838137 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764567 SCV000895655 uncertain significance Desmoid disease, hereditary; Carcinoma of colon; Familial adenomatous polyposis 1; Neoplasm of stomach; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211923 SCV000918453 benign not specified 2021-04-24 criteria provided, single submitter clinical testing Variant summary: APC c.5801C>T (p.Pro1934Leu) results in a non-conservative amino acid change located in the 20-amino acid beta-catenin down-regulating repeats (20AAR) (Azzopardi_APC_Cancer Res_2008) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 249974 control chromosomes, predominantly at a frequency of 0.00041 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.5801C>T has been reported in the literature in individuals affected with multiple colorectal adenomas (Azzopardi 2008), and in other patients with various tumor phenotypes (Zhang 2015, Shirts 2015, Pritchard 2018). In one of these reports, this variant occurred in the germline of a patient with hypodiploid ALL and is unlikely to have been the primary causative lesion associated with the patient presentation (Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Azzopardi 2008). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; VUS, n=9). At-least two additional submitters have re-classified this variant as likely benign/benign since our previous evaluation. One submitter cites an unspecified co-occurrence with a mutation in another gene that clearly explains a proband's phenotype. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services,Illumina RCV001155575 SCV001317012 uncertain significance APC-Associated Polyposis Disorders 2019-03-08 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Genetic Services Laboratory,University of Chicago RCV000211923 SCV002066674 uncertain significance not specified 2020-11-12 criteria provided, single submitter clinical testing This sequence change has been described in the gnomAD database with a global population frequency of 0.014% and 0.04% in the Latino sub population (dbSNP rs587780600). This sequence change has been reported in some patients with colorectal adenoma, one patient with adenomatous colorectal polyps and one patient with bilateral breast cancer (PMIDs: 21859464, 18199528 and 26845104). There is some experimental evidence that does not demonstrate damaging effect for this variant (PMID 18199528). The p.Pro1934Leu change affects a highly conserved amino acid residue located in the 20-amino acid repeat beta-catenin down-regulating domain as well as the SAMP repeats/axin binding domain (PMID 18199528). In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro1934Leu substitution. Due to these contrasting evidences, the clinical significance of the p.Pro1934Leu change remains unknown at this time.
CeGaT Center for Human Genetics Tuebingen RCV000656747 SCV002497339 likely benign not provided 2022-03-01 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000159562 SCV002528010 likely benign Hereditary cancer-predisposing syndrome 2021-12-18 criteria provided, single submitter curation

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