ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1604C>T (p.Ser535Phe) (rs75870842)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000035065 SCV000058705 uncertain significance not specified 2010-04-01 criteria provided, single submitter clinical testing
GeneDx RCV000035065 SCV000209495 likely benign not specified 2017-12-05 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000159535 SCV000214634 likely benign Hereditary cancer-predisposing syndrome 2017-12-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,Subpopulation frequency in support of benign classification
Invitae RCV000034404 SCV000218646 likely benign not provided 2019-03-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000035065 SCV000600045 uncertain significance not specified 2017-04-19 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000035065 SCV000694001 likely benign not specified 2019-09-06 criteria provided, single submitter clinical testing Variant summary: APC c.1604C>T (p.Ser535Phe) results in a non-conservative amino acid change located in the Armadillo domain (IPR000225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250770 control chromosomes, predominantly at a frequency of 0.0023 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 32 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 African or African-American origin. The variant, c.1604C>T, has been reported in the literature in individuals being tested for familial adenomatous polyposis or patients affected with endometrial or breast cancer (e.g. Kerr_2013, Ring_2016, Torrezan_2018). These reports 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2x VUS, 4x likely benign). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000144567 SCV000838078 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000159535 SCV000903018 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034404 SCV000043111 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Pathway Genomics RCV000144567 SCV000189860 uncertain significance Familial adenomatous polyposis 1 2014-07-24 no assertion criteria provided clinical testing

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