ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7399C>A (p.Pro2467Thr) (rs372305287)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120031 SCV000149029 likely benign not specified 2018-02-12 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 RCV000115120 SCV000213856 likely benign Hereditary cancer-predisposing syndrome 2018-06-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Invitae RCV000148360 SCV000254035 likely benign Familial adenomatous polyposis 1 2019-12-31 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000120031 SCV000257788 uncertain significance not specified 2015-06-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120031 SCV000591207 uncertain significance not specified 2016-08-12 criteria provided, single submitter clinical testing
Color RCV000115120 SCV000681864 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120031 SCV000694114 likely benign not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: APC c.7399C>A (p.Pro2467Thr) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) 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 0.00012 in 278198 control chromosomes. The observed variant frequency is approximately 1.7 fold above the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05). Additionally, in the Ashkenazi Jewish subpopulation, the variant frequency is more than 12 fold above the estimated maximal expected allele frequency, strongly suggesting the variant is benign. c.7399C>A has been reported in the literature in individuals affected with colorectal cancer, familial adenomatous polyposis, Lynch syndrome or HBOC, without strong evidence of causality (e.g. Azzopardi_2008, Yurgelun_2015, Zidan_2017). These reports do not provide unequivocal conclusions about an association of the variant with Familial Adenomatous Polyposis. However, it has been reported to co-occur with a presumably pathogenic APC-LOF variant and APC-LOH deletion in a colorectal cancer tumor derived specimen. In this study, truncating APC mutations and/or LOH were detected in 75% of CRC's examined supporting a benign role for this variant in disease pathogenesis. Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (8x uncertain significance and 3x likely benign). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120031 SCV000711955 uncertain significance not specified 2016-11-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign.
PreventionGenetics,PreventionGenetics RCV000590816 SCV000805464 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Mendelics RCV000148360 SCV000838148 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000735966 SCV000864155 uncertain significance Colorectal cancer 2016-06-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 51 year old male diagnosed with colon cancer at age 50. Family history of colorectal cancer and/or polyps. Patient also has the APC c.5026A>G variant. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590816 SCV001133365 likely benign not provided 2019-03-22 criteria provided, single submitter clinical testing
ITMI RCV000120031 SCV000084162 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148360 SCV000190050 likely benign Familial adenomatous polyposis 1 2014-06-01 no assertion criteria provided research
True Health Diagnostics RCV000115120 SCV000787839 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing
Molecular Oncology Laboratory,Hospital Clínico San Carlos RCV000148360 SCV000844925 uncertain significance Familial adenomatous polyposis 1 2018-06-01 no assertion criteria provided clinical testing

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