ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.2090C>G (p.Pro697Arg) (rs36120395)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000988952 SCV000289287 likely benign Colorectal cancer, susceptibility to, 12 2019-12-30 criteria provided, single submitter clinical testing
GeneDx RCV000657066 SCV000293173 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing This variant is denoted POLE c.2090C>G at the cDNA level, p.Pro697Arg (P697R) at the protein level, and results in the change of a Proline to an Arginine (CCC>CGC). This variant was identified in at least two individuals with a personal and/or family history of cancer (Cabanillas 2017, Mandelker 2017). POLE Pro697Arg was observed at an allele frequency of 0.15% (190/125,844) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the polymerase domain (Preston 2010). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether POLE Pro697Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235798 SCV000540090 uncertain significance not specified 2016-10-13 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: Variant not in HGMD, conflicting classifications in ClinVar. MaxMAF = 0.13%. AA not conserved but Arg not in any species.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235798 SCV000601995 uncertain significance not specified 2017-01-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565117 SCV000671278 uncertain significance Hereditary cancer-predisposing syndrome 2015-05-15 criteria provided, single submitter clinical testing Insufficient or inconclusive evidence
PreventionGenetics,PreventionGenetics RCV000657066 SCV000806739 likely benign not provided 2017-05-04 criteria provided, single submitter clinical testing
Mendelics RCV000709270 SCV000838701 uncertain significance COLORECTAL CANCER 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988952 SCV001138893 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235798 SCV001370689 likely benign not specified 2020-05-26 criteria provided, single submitter clinical testing Variant summary: POLE c.2090C>G (p.Pro697Arg) results in a non-conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00091 in 249370 control chromosomes in the gnomAD database, including 1 homozygotes. The observed variant frequency is approximately 64 fold of the estimated maximal expected allele frequency for a pathogenic variant in POLE causing Colorectal Cancer phenotype (1.4e-05), strongly suggesting that the variant is benign. c.2090C>G has been reported in the literature in sequencing studies of individuals affected with colorectal cancer, and breast cancer (example, Bonache_2018, Kothari_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Colorectal Cancer. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory ( BRCA2 c.4271delC , p.Ser1424LeufsX24), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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=2; VUS, n=7). Based on the evidence outlined above, the variant was classified as likely benign.
True Health Diagnostics RCV000565117 SCV000788165 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-30 no assertion criteria provided clinical testing

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