ClinVar Miner

Submissions for variant NM_006231.4(POLE):c.3046G>A (p.Val1016Met) (rs147692158)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000988944 SCV000261875 likely benign Colorectal cancer, susceptibility to, 12 2020-12-02 criteria provided, single submitter clinical testing
GeneDx RCV000585364 SCV000293081 likely benign not provided 2020-10-29 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 28873162, 21701589, 29458332)
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235475 SCV000540094 uncertain significance 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 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 at a MaxMAF of 0.15% (high for disease incidence and gene contribution).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585364 SCV000602024 benign not provided 2019-02-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000562355 SCV000671246 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-19 criteria provided, single submitter clinical testing Thep.V1016M variant (also known as c.3046G>A), located in coding exon 25 of thePOLE gene, results from a G to A substitution at nucleotide position 3046. The valine at codon 1016 is replaced by methionine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs147692158. Based on data from the 1000 Genomes Project, the A allele has an overall frequency of approximately 0.05% (1/2098) total alleles studied. The highest observed frequency was 0.59% (1/170) British alleles. Based on data from the NHLBI Exome Sequencing Project (ESP), the A allele has an overall frequency of approximately 0.09% (12/13006) total alleles studied, having been observed in 0.05% (2/4406) African American alleles and 0.12% (10/8600) European American alleles. To date, this alteration has been detected with an allele frequency of approximately 0.082% (greater than 25000 alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be benign and deleterious byPolyPhenand SIFTinsilicoanalyses, respectively. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000585364 SCV000692767 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000585364 SCV000806756 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing
Mendelics RCV000709263 SCV000838694 uncertain significance Familial colorectal cancer 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988944 SCV001138881 uncertain significance Colorectal cancer, susceptibility to, 12 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000235475 SCV001361502 likely benign not specified 2019-05-14 criteria provided, single submitter clinical testing Variant summary: POLE c.3046G>A (p.Val1016Met) results in a conservative amino acid change located in the DNA-directed DNA polymerase, family B, multifunctional domain (IPR006134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00078 in 248236 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 55 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.3046G>A has been reported in the literature in individuals affected with various tumor phenotypes, e.g. colorectal cancer and cutaneous melanoma, but without strong evidence of causality (Dominguez-Valentin_2018, Pritchard_2018). 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, one classified as likely benign while the others classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
True Health Diagnostics RCV000562355 SCV000886710 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-07 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357617 SCV001553138 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The POLE p.Val1016Met variant was not identified in the literature nor was it identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs147692158) as “With Uncertain significance allele” and ClinVar (as likely benign by Invitae, and uncertain significance by GeneDx, Laboratory for Molecular Medicine Partners Health Care Personalized Medicine, Quest Diagnostics and Ambry Genetics). The variant was identified in control databases in 206 of 273880 chromosomes (1 homozygous) at a frequency of 0.0008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 5 of 24010 chromosomes (freq: 0.0002), Other in 6 of 6400 chromosomes (freq: 0.0009), Latino in 8 of 34170 chromosomes (freq: 0.0002), European (Non-Finnish) in 172 of 124734 chromosomes (freq: 0.001), Finnish in 15 of 25468 chromosomes (freq: 0.0006); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Val1016 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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