ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.4523G>A (p.Arg1508His) (rs142508245)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000988934 SCV000289389 likely benign Colorectal cancer, susceptibility to, 12 2019-12-31 criteria provided, single submitter clinical testing
GeneDx RCV000590106 SCV000293174 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted POLE c.4523G>A at the cDNA level, p.Arg1508His (R1508H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been observed as a somatic variant in a tumor sample, although the tumor type was not reported (Cheng 2015). POLE Arg1508His was observed at an allele frequency of 0.23% (54/23,804) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether POLE Arg1508His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000236616 SCV000540088 likely benign not specified 2016-10-31 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is not present in HGMD and has not been reported in affected individuals. It is classified in ClinVar with 1 star as Likely Benign by Invitae and VUS by GeneDx. It is present in ExAC with a frequency of 0.27% (high frequency for disease incidence and gene contribution). 2 mammals have a Histidine at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236616 SCV000602048 uncertain significance not specified 2017-03-25 criteria provided, single submitter clinical testing
Ambry Genetics RCV000566255 SCV000671258 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-24 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000590106 SCV000698668 benign not provided 2017-06-23 criteria provided, single submitter clinical testing Variant summary: The POLE c.4523G>A (p.Arg1508His) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 128/120124 control chromosomes at a frequency of 0.0010656, which is approximately 75 times the estimated maximal expected allele frequency of a pathogenic POLE variant (0.0000142), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. An internal LCA sample reports the variant to co-occur with two pathogenic MUTYH variants, c.1187G>A and c.536A>G. Taken together, this variant is classified as benign.
PreventionGenetics,PreventionGenetics RCV000590106 SCV000806784 uncertain significance not provided 2017-06-20 criteria provided, single submitter clinical testing
Mendelics RCV000709254 SCV000838685 uncertain significance COLORECTAL CANCER 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988934 SCV001138867 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000566255 SCV000805301 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-15 no assertion criteria provided clinical testing

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