ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2593C>T (p.Pro865Ser)

gnomAD frequency: 0.00028  dbSNP: rs192620988
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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV003743577 SCV000166021 benign Familial adenomatous polyposis 1 2024-02-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131163 SCV000186108 likely benign Hereditary cancer-predisposing syndrome 2019-01-25 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
GeneDx RCV000587302 SCV000209504 likely benign not provided 2020-12-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27124905, 21859464, 14695993, 31159747)
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia RCV000238728 SCV000297018 uncertain significance Familial multiple polyposis syndrome 2015-09-24 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000348086 SCV000451998 likely benign APC-Associated Polyposis Disorders 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000122764 SCV000487865 uncertain significance Familial adenomatous polyposis 1 2015-11-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587302 SCV000600060 likely benign not provided 2023-02-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002228418 SCV000694015 likely benign not specified 2022-04-09 criteria provided, single submitter clinical testing Variant summary: APC c.2593C>T (p.Pro865Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.5e-05 in 282448 control chromosomes. The observed variant frequency is approximately 1.2 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 benign. c.2593C>T has been reported in the literature in an individual with microsatellite unstable (MSI) sporadic colorectal cancer due to MLH1 promoter hypermethylation and in settings of multigene panel testing of clinical tumor samples (example, Domingo_2004, Goswami_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve 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 (Likely benign/Benign, n=7; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA RCV000131163 SCV000821810 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000131163 SCV000910647 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Mendelics RCV003492529 SCV001136895 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000587302 SCV001471856 likely benign not provided 2019-10-08 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000587302 SCV002010892 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000131163 SCV002538337 uncertain significance Hereditary cancer-predisposing syndrome 2021-10-01 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000587302 SCV002544970 likely benign not provided 2022-05-01 criteria provided, single submitter clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV000122764 SCV003843141 uncertain significance Familial adenomatous polyposis 1 2022-11-03 criteria provided, single submitter clinical testing The APC c.2593C>T (p.Pro865Ser) missense change has a maximum non-founder subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in an individual referred for genetic testing for hereditary cancer predisposition (PMID: 31159747). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000131163 SCV004228075 benign Hereditary cancer-predisposing syndrome 2024-01-04 criteria provided, single submitter clinical testing

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