ClinVar Miner

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

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Total submissions: 11
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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 likely benign not specified 2019-05-02 criteria provided, single submitter clinical testing The p.Ser535Phe variant in APC is classified as likely benign because it has been identified in 0.23% (58/24966) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has been reported in ClinVar by several laboratories (Variation ID 41519). While it has been identified in 1 individual who underwent testing APC testing (Kerr 2013), its frequency is too high to be consistent with a pathogenic variant causative for familial adenomatous polyposis.
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 2018-12-24 criteria provided, single submitter clinical testing Other strong data supporting benign classification;Subpopulation frequency in support of benign classification
Invitae RCV000144567 SCV000218646 benign Familial adenomatous polyposis 1 2020-11-25 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000035065 SCV000694001 likely benign not specified 2020-09-14 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. 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. Eight 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, n=5, VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. 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 Health, Inc RCV000159535 SCV000903018 likely benign Hereditary cancer-predisposing syndrome 2016-12-08 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000035065 SCV001158109 uncertain significance not specified 2018-12-31 criteria provided, single submitter clinical testing The APC c.1604C>T; p.Ser535Phe variant (rs75870842) is reported in the literature in at least one individual affected with familial adenomatous polyposis, and in a large cancer cohort (Johnston 2012, Kerr 2013). This variant is reported as uncertain significance or likely benign by multiple laboratories in ClinVar (Variation ID: 41519), and is found in the African population with an allele frequency of 0.23% (58/24,966 alleles) in the Genome Aggregation Database. The serine at codon 535 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of the p.Ser535Phe variant is uncertain at this time. References: Johnston JJ et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43.
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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