ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2593C>T (p.Pro865Ser) (rs192620988)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122764 SCV000166021 uncertain significance Familial adenomatous polyposis 1 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 865 of the APC protein (p.Pro865Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs192620988, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 135690). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000131163 SCV000186108 likely benign Hereditary cancer-predisposing syndrome 2018-01-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Subpopulation frequency in support of benign classification,in silico models in agreement (benign)
GeneDx RCV000587302 SCV000209504 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing This variant is denoted APC c.2593C>T at the cDNA level, p.Pro865Ser (P865S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). This variant has been observed in the tumor of an individual with a BRAF-positive colon cancer and no significant family history (Domingo 2004). APC Pro865Ser was observed at an allele frequency of 0.06% (6/10,134) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. APC Pro865Ser occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether APC Pro865Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238728 SCV000297018 uncertain significance Familial multiple polyposis syndrome 2015-09-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 RCV000211903 SCV000600060 uncertain significance not specified 2017-02-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587302 SCV000694015 likely benign not provided 2016-03-14 criteria provided, single submitter clinical testing
GeneKor MSA RCV000131163 SCV000821810 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000131163 SCV000910647 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
Mendelics RCV000122764 SCV001136895 uncertain significance Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing

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